Woburn, MA (August 8th, 2023) — In a monumental leap forward for Shwachman-Diamond Syndrome research, treatment, and patient care, the Shwachman-Diamond Syndrome Alliance is thrilled to announce that the US version of the authoritative international diagnostic manual will soon include a unique diagnostic code for Shwachman-Diamond Syndrome — a rare genetic disorder with often devastating outcomes for patients, first described in 1964.

In its latest revision, the International Classification of Diseases, Clinical Modification (or ICD-10-CM) officially recognizes Shwachman-Diamond Syndrome as a distinct disease, with code D61.02 going live October 2023. This change could pave the way for improved treatments, novel therapies, and someday a cure.

Dr. Eszter Hars, Ph.D, President and CEO of SDS Alliance, elaborates: “This represents a major milestone for the SDS community; one that will be instrumental in future progress for better understanding and better treatments for SDS patients worldwide. By assigning this ICD-10-CM code, the CDC is formally recognizing SDS as a discrete and important disease worthy of tracking and coding in the ICD system, and that will make a life-altering difference for people affected by the condition.”

Previously, SDS was not coded as such in medical records. Instead, healthcare professionals resorted to using general ICD-10 codes, which encompass multiple conditions or individual symptoms but aren't custom tailored for SDS. While such codes may have sufficed for insurance purposes, they fell short when it came to tracking or understanding the journey of SDS patients within healthcare systems. SDS was essentially invisible.

Dr. Hars explains further, “This specific and unique code for SDS will help provide invaluable insights and data into the number of patients, the range and severity of symptoms, as well as the types and timing of treatments, testing, and services they receive, and the outcomes of those interventions. It will also help simplify and streamline the insurance reimbursement process for patients and make it easier to receive the most appropriate and beneficial medical care, tests, treatments, therapies, and services.”

Most importantly, Dr. Hars stresses, the change will help accelerate therapy development by capturing new data that is crucial for driving further investments in research.

“The newly approved ICD-10 code for Shwachman-Diamond Syndrome will improve patient care for individuals with SDS,” said Dr. Lisa McReynolds, of the National Cancer Institute, part of the National Institutes of Health. “Insurance approvals will be easier to process, and medical records will be standardized, facilitating research on this rare syndrome. This is a milestone achievement for the SDS Alliance that will benefit all SDS patients, including those enrolled in the NCI Inherited Bone Marrow Failure Syndrome study (NCT00027274).”

Shwachman-Diamond Syndrome: A Brief Overview

Shwachman-Diamond Syndrome is a distinct genetic condition characterized by the body's inability to produce adequate amounts of protein, which plays a pivotal role in every cellular and organ function and is fundamental to life. Consequently, many of the body's systems are adversely impacted in SDS patients.

To create new proteins, the body relies on sub-cellular structures called ribosomes to perform the complex assembly. Ribosomes work much like hands assembling LEGO towers, but instead of plastic blocks, they stack amino acids in specific patterns to build a variety of proteins. The specific sequence of amino acids, as determined by the genetic code found in DNA, is what dictates the proteins’ three-dimensional shape and, ultimately, their function.

A genetic anomaly found in SDS patients results in their cells being unable to form enough functional ribosomes, leading to an overall decline in protein synthesis. This deficiency manifests differently across patients and their respective organs, resulting in a range of symptoms.

Many individuals with SDS encounter digestive issues and pancreatic challenges that can lead to malnutrition, pain, and failure to thrive. Others face complications with their immune system, making them prone to frequent or severe infections and hospitalization. Additionally, some patients grapple with cognitive issues, which can cause learning and behavioral challenges.

Notably, by the age of 30, approximately one-third of those with SDS will confront grave complications related to their bone marrow, such as aplastic anemia and leukemia — the latter being particularly alarming due to its dire prognosis.

Diagnostic challenges can further complicate matters. A significant number of SDS patients face misdiagnoses or endure prolonged waiting periods before receiving an accurate diagnosis. Such delays can result in undue distress, unnecessary invasive procedures, ineffective treatments, and in grave cases, even death from leukemia and other associated complications.

The most reliable method for diagnosing SDS is genetic testing; specifically, identifying the presence of mutations in the SBDS or other genes responsible for the disorder. For the well-being and longevity of SDS patients, it's imperative that diagnosis is both swift and precise.

The Long, Arduous Path to ICD-10-CM Classification

The path to obtaining a new code for a previously unclassified disorder involves a long and challenging process.

In the US, the CDC’s ICD-10 Coordination and Maintenance Committee selects proposals for live presentations either at its headquarters in Baltimore or virtually twice a year. In December 2021, the SDS Alliance, aided by Medical Advisory Board member and NICER consortium director Dr. Kelly Jo Walkovich, University of Michigan, C.S. Mott Children's Hospital, along with collaborator Dr. Alison A. Bertuch, Texas Children's Hospital and Baylor College of Medicine, submitted a proposal for a new code. Their proposal was then selected for presentation at the March 2022 meeting. During the public comment period that followed, major organizations such as the NIH IBMF study, the American Society of Hematology, the Leukemia and Lymphoma Society, the Aplastic Anemia & MDS International Foundation, and The American Society of Pediatric Hematology/Oncology, submitted letters of support. The new code was officially accepted in July 2023 and will be active starting October 1st, 2023.

The SDS Alliance credits Dr. Terry Jo Bichell from COMBINEDBrain for her guidance and support throughout the effort.

Dr. Bichell explains, “Because rare genetic disorders like SDS will likely be treated based on their underlying genetics and molecular mechanism, unique ICD-10 codes for each genetic disorder are crucial to identify, track and treat patients. This new code will help patients with SDS get the medical care they need. We at COMBINEDBrain are proud of the SDS Alliance for their work on this, and we are grateful to the CDC committee for recognizing the necessity of a code for Shwachman-Diamond Syndrome.”

The International Classification of Disease

The ICD is a collaborative effort by the World Health Organization, the Centers for Medicare and Medicaid Services, and the Centers for Disease Control and Prevention. It is a global tool that allows medical professionals, insurers, and public health experts to categorize and code healthcare-related encounters. Launched by WHO in 1948, the ICD has seen multiple revisions. The 10th version was ratified in 1994, with US adoption following later. While the WHO approved the updated ICD-11 for introduction in 2022, US adoption will likewise lag by a few years. In the meantime, the US continues with ICD-10, ensuring the newly added SDS code remains active.

The Shwachman-Diamond Syndrome Alliance

The SDS Alliance is a 501(c)(3) nonprofit organization dedicated to building a world where all patients affected by Shwachman-Diamond Syndrome can live full lives. The SDS Alliance focuses on driving research and paving the path toward therapies and cures by funding and coordinating research, building research tools and infrastructure, and fostering advocacy, collaboration, and knowledge sharing. The SDS Alliance brings together patients, caregivers, researchers, clinicians, and other diverse stakeholders to better understand, diagnose, and treat this devastating genetic cancer predisposition disorder. The SDS Alliance was launched in 2020 by the parents of a child with SDS, both of whom are biomedical researchers and entrepreneurs. Learn more at ,www.SDSAlliance.org

North American Immuno-Hematology Clinical Education & Research Consortium (NICER)

The mission of the NICER consortium is to provide a collaborative multidisciplinary environment to advance the education, clinical care, and research involving pediatric and adult patients with immuno-hematologic disorders. The target patient population encompasses all disorders within immuno-hematology including those with complex immune cytopenias, bone marrow failure, lymphoproliferative and histiocytic disorders, immune deficiencies, autoinflammatory disorders and immune dysregulatory syndromes along with emerging phenotypes of a similar nature. Given that institutional referral patterns and expertise vary, NICER is committed to being purposefully inclusive of pediatric and adult providers from multiple disciplines including, allergy/immunology, genetics, hematology/oncology, hematopoietic stem cell transplant, rheumatology, infectious disease, gastroenterology, endocrinology, etc. to enrich the educational environment and research goals of the consortium. Learn more at ,www.nicerconsortium.org/

NCI Inherited Bone Marrow Failure Syndrome Study (NCT00027274)

Inherited bone marrow failure syndromes are a group of rare disorders of the bone marrow that can result in a number of medical conditions, including a high risk of cancer. Over the past several decades, researchers and clinicians at the National Cancer Institute have studied individuals with these syndromes in order to better understand their genetic causes and medical complications. Their overall goal is to improve the health care for persons with these disorders. The NCI IBMFS Cohort Study enrolls families that have at least one member with an IBMFS, such as Shwachman-Diamond Syndrome. There have been many medical advances as a result of the study, including the identification of several new genetic causes of IBMFS. Learn more at ,www.marrowfailure.cancer.gov/ibmfs

COMBINEDBrain

The Consortium for Outcome Measures and Biomarkers for Neurodevelopmental Disorders is a non-profit organization devoted to speeding the path to clinical treatments for people with rare genetic neurodevelopmental disorders by pooling efforts, studies and data.

More Information

Visit the ICD resource page of the SDS Alliance at www.sdsalliance.org/icd

Media Contact

Eszter Hars, Ph.D.

President and CEO, Shwachman-Diamond Syndrome Alliance

connect@SDSAlliance.org

Jennifer passed away from complications of Shwachman-Diamond Syndrome. Jen was loved by everyone she met, she cared and loved deeply. Shwachman Diamond took a huge toll on her the last 10 years, especially the last two years of her life. A bone marrow transplant was discussed, but her health never stabilized enough to initiate a transplant. Rest in peace, Jenni.

Obituary

Jennifer Anne Reutlinger of Peterborough NH passed away July 6, 2023, from a blood disorder, Myelodysplastic Syndrome (MDS), which developed from a rare genetic disorder known as Schwachman-Diamond Syndrome, (SDS). She was 37 years old. Jennie lived most of her youth living in Greenfield, and Peterborough, NH. After high school, she attended the Job Corps Northlands campus in Vergennes, VT, and the Culinary Institute at Macintosh College, before receiving her phlebotomy license. She lived in Manchester NH for a short while, before returning to Peterborough.

Jennie was a curious child who loved exploring her natural world, camping and caving with family and friends. She enjoyed spending time with her friends and watching her favorite movies, while snuggling with her cats. As she grew into adulthood, complications from SDS became more apparent, hindering her ability to maintain an active and fulfilling life she had dreamed. Although the struggles of her illness became more challenging, Jennie still remained a source of positivity, strength and kindness to others, no matter how ill she felt. Jennie often opened her home and her heart to those in need of a hand up. Even in the last months of her illness, she often shared words of support and encouragement to others who needed it. The love she held for her family and friends helped give her the courage to fight the rare blood disease MDS.

She is treasured by all who knew her and will be dearly missed.

Rycroft passed away last month at the age of 16 months following a bone marrow transplant, which was needed due to Shwachman-Diamond Syndrome (SDS). His parents are sharing his story to raise funds for the hospitals that provided outstanding care for Rycroft and their local SDS organization (SDS UK) which provided support during Rycroft's challenging SDS journey.

Rycroft's parents Andrew and Catherine shared the heartbreaking news on Twitter:

Rycroft was a happy, shouty, beautiful little boy and it seemed like everyone that met him fell in love with him. He loved to crawl, even though his condition made it hard for him to lift his head. So he crawled backwards and upside down. He was surprisingly speedy.

Rycroft was a world champion sleeper. With no soothing or assistance of any kind from us, he could be sparko in seconds. He would wrap his favourite toy, BunBun, around his head and that was the sign he was off to . BunBun is still with him now, friends to the end.

Rycroft seemed to like Status Quo and other DadRock. He'd certainly bash his toys along to the music. If that was actually a sign you wanted it turned off, then sorry Rycroft.

People with SDS are much more likely to need bone marrow transplants than the general population. We think Rycroft may have been the youngest SDS patient in the UK ever to receive one, and perhaps the third youngest worldwide.

The transplant went well, but he later developed an infection in his lungs, and was transferred to ICU. He had to be sedated and put onto a ventilator. I found it difficult to be with him, him virtually motionless, me feeling like a spare part during my son's toughest hours.

What I found really helped was reading to him. I read him all of William the Conqueror by Richmal Crompton. Like William, Rycroft was a little boy with a dog called Jumble. And as

@monstroso says in his introduction, William is what every boy wants to be, a hero. As was Rycroft.

There came a point where we realised that Rycroft was not going to recover.

@GreatOrmondSt were amazing at taking us through that realisation. When Rycroft died, it was peacefully in our arms. We got the chance to tell him how much we loved him and how much he means to us.

It's hard to believe that we will never see him again. But in sixteen months, he gave us a lifetime's worth of happiness.

Right now, we really want to do what we can to support other families like ours, other children like Rycroft, through [three charities we chose]. Whatever you can give, whatever you can do to share, spread the word - thank you.

Andrew and Catherine set up a JustGiving fundraising page in memory of Rycroft:

Our beautiful baby boy Rycroft passed away aged just 16 months. He was a smiley, sociable and inspirational little boy who charmed everyone who met him. Rycroft suffered from Shwachman Diamond Syndrome (SDS), a rare genetic condition that affects multiple systems within the body and, in a quarter of cases, results in bone marrow failure. For a huge proportion of his short life he was cared for by the wonderful team on the children’s ward at Colchester General Hospital. In March 2023 he was admitted to Great Ormond Street Hospital for a bone marrow transplant – and although the transplant was initially successful, he passed away a few months later after contracting a subsequent infection. We are devastated by his loss and want to raise funds to help other families who may go through what we have been through, and to raise awareness of the incredible work of the medical professionals who cared for him. We have chosen three charities that do amazing work to help children like Rycroft survive and thrive. Great Ormond Street Hospital, Fox Ward Colchester Hospital, Children's Ward SDS UK All funds donated will be split evenly and will go to support these charities, who played such a huge role in giving Rycroft and us 16 wonderful months together, and give us hope that other families in a similar position will see their children grow up to live full and happy lives. Thank you, Andrew and Catherine

Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

New proof-of-concept article on RNA Therapeutics and Base/Prime Editing for SDS

Last month, Dr. Balestra and colleagues in Italy published the first of its kind article summarizing the results of several different SDS specific therapeutic strategies. This work was in part supported by the Italian SDS patient advocacy group, AISS. The first half of the article focuses on approaches targeting RNA in SDS cells, while the second half covers DNA targeting approaches.

The American Society of Gene & Cell Therapy has some fantastic resources to help patients understand what cell and gene therapy is. Check out their recourses (videos, graphics, etc) on the Gene Therapy 101 page. We also have many educational resources on our Understanding SDS Science page.

We reached out to Dr. Balestra to bring you an exclusive summary of their work.

Here is the summary of the work they shared:

Counteracting the Common Shwachman-Diamond Syndrome-Causing SBDS c.258+2T>C Mutation by RNA Therapeutics and Base/Prime Editing

Shwachman–Diamond syndrome (SDS) is a rare recessive autosomal disease and one of the most common inherited bone marrow failure syndromes. SDS is caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene, that encodes the homonymous protein SBDS.

Among the over 20 different causative mutations, the c.258+2T>C variant is one of the most common and it originates from gene conversion events with the pseudogene copy (SBDSP), which shares 97% of nucleotide homology with SBDS. This splicing mutation impairs messenger RNA processing, thus leading to synthesis of a dysfunctional shorter SDS protein isoform.

Only supportive treatments are available for SDS patients, with hematopoietic cell transplantation required when bone marrow failure occurs. Therefore, novel therapeutic strategies are highly desirable.

Here, we investigated the molecular mechanisms underlying aberrant SBDS splicing and explored different correction approaches at the DNA and RNA levels, such as engineered U1snRNA, trans-splicing molecules and Base/Prime Editors (BE and PE, respectively).

A little summary on splicing mechanism

Eukaryotic genes consist of coding sequences (“exons”) periodically interrupted by non-coding sequences (“introns”). After transcription of the gene into messenger RNA (mRNA), the pre-mRNA is processed by a huge macromolecular complex (called spliceosome) to remove the introns and thus originate the mature mRNA. Exons and introns are defined by specific nucleotide sequences that dictate where the splicing take place. The 5’ end of the intron (5’ splice site; 5’ss) is characterized by a highly conserved GT sequence and in the earlier splicing step it is recognized by U1snRNP through base pair complementarity with its U1snRNA component.

Since the SBDS c.258+2T>C mutation occurs within the highly conserved 5’ss GT dinucleotide of SBDS exon 2, it is commonly considered a null mutation, with no production of correct SBDS transcripts and thus proteins. However, genetic and animal studies indicate that the complete absence of SBDS is virtually incompatible with life. Therefore, we initially investigated in cells derived from a SDS patient the presence of trace levels of correctly SBDS spliced RNA. Studies at RNA level enabled us to demonstrate the presence of trace levels (~2%) of correctly spliced transcripts, a finding explaining the survival of homozygous patients for this mutation.

Development of RNA therapeutics for SBDS c.258+2T>C mutation

In the attempt to increase total amount of SBDS correctly spliced transcripts, we explored two RNA therapeutics acting on pre-mRNA.

The approach based on engineered U1snRNAs is aimed at restoring proper SBDS exon 2 5’ss recognition and thus correct splicing. The screening of a panel of engineered U1snRNAs identified one U1snRNA variant able to partially restore the usage of the mutated 5’ss, with correctly spliced transcripts increasing from barely detectable to 2,5% of the total transcripts.

On the other hand, since most of the causative SDS mutations are located within the SBDS exon 2 or in the downstream exons, we envisioned to develop a therapeutic strategy aimed at replacing, at RNA level, the coding sequence spanning SBDS exon 2 to exon 4. To this aim, we exploited the trans-splicing process, where the splicing occurs between two different RNA molecules. To trigger this process, we developed 3’ pre-trans splicing molecule (PTM). Worth noting that, due to the high homology between SBDS and SBDSP pseudogene, both transcripts can be targeted with this approach at the same time, thus increasing the possible amount of correctly spliced transcripts. We demonstrated in vitro that our PTMs can trigger the trans-splicing of our therapeutic cassette with either SBDS or SBDSP, but quantification of trans-spliced transcripts by specific qPCR was unfeasible due to the cellular model exploited.

Overall, these data provide the first proof of principle of the U1snRNA/PTM-based correction of SBDS c.258+2T>C mutation and encourage further research aimed at optimizing these approaches.

Development of Base/Prime Editing for SBDS c.258+2T>C mutation

To permanently revert the SBDS c.258+2T>C mutation at DNA level with a single intervention, and thus develop a “hit and run” correction approach, we exploited Base and Prime Editors. These strategies are based on state-of-the-art variants of the famous CRISP/Cas9 protein, largely exploited to make precise genetic manipulations. We tested a panel of BE and PE editors and demonstrated that all of them corrected the mutation, as witnessed by the appearance of correctly spliced transcripts. In particular, one of these editors led to 5% of correct. Overall, this represents the first proof of-principle of the Base/Prime Editors-mediated correction of the c.258+2T>C mutation that would be permanent, transmitted to the daughter’s cells in proliferating tissues such as the bone marrow, and would maintain the physiological SBDS gene regulation. These data encourage further researches aimed at optimizing this approach by exploring viral and non-viral delivery as well as novel generations of DNA editors, combined with the careful evaluation of target specificity. This could eventually lead to an innovative “SDS personalized therapy” based on the autologous transplantation of edited hematopoietic stem cells.

Counteracting the Common Shwachman-Diamond Syndrome-Causing SBDS c.258+2T>C Mutation by RNA Therapeutics and Base/Prime Editing.

Peretto L, Tonetto E, Maestri I, Bezzerri V, Valli R, Cipolli M, Pinotti M, Balestra D.

Int J Mol Sci. 2023 Feb 16;24(4):4024.

doi: 10.3390/ijms24044024.

PMID: 36835434

New review of diagnostic testing for Exocrine Pancreatic Insufficiency (EPI)

As you all know, Shwachman Diamond syndrome is a rare, autosomal recessive, inherited disorder in ribosomal biogenesis that results in bone marrow failure and Exocrine pancreatic Insufficiency (EPI). Pancreatic issues are thought to be due to acinar cell hypoplasia, that is, damage or displacement of the acinar cells in the pancreas. The pancreatic acinar cell is a highly specialized structure developed for synthesis, storage, and secretion of digestive enzymes. More here.

EPI in SDS patients is typically seen within the first 6 to 12 months of life, with variable severity. In about half of patients, the symptoms improve by age 5, but may return later in life. Patients may also have skeletal defects, such as short stature and poor growth, and frequent infections due to bone marrow failure. SDS is the second most common cause of

EPI in children after Cystic Fibrosis (CF).

This new review article offers an overview of the various testing methods for EPI, with a discussion of the advantages, drawbacks, and recommendations.

Inherited causes of exocrine pancreatic insufficiency in pediatric patients: clinical presentation and laboratory testing.

Yuzyuk TN, Nelson HA, Johnson LM. Crit Rev Clin Lab Sci. 2023 Mar 6:1-16.

doi: 10.1080/10408363.2023.2179968.

PMID: 36876586

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Moe passed away from complications of stem cell transplantation 200 days post transplant, surrounded by his family. He leaves behind his wife, two teenage daughters, his parents and siblings, and countless family and friends.

If you would like to support his family, please consider donating to the GoFundMe page the family has set up at the start of his transplant journey: ,https://gofund.me/7909aa8d

Here is what the family shared:

July 23, 2022

"We are starting a Go Fund Me with the recommendation of his Team.

It was recommended because this procedure is going to be financially difficult for Moe and Lauren. As a family we prepared by allocating and coordinating food shopping, electric bills, heating bills, future bills, etc. but not prepared for the astronomical costs involved for his month long chemo stay, the 35 daily oral medicines, co-pays and daily organ protection injections. The cost is projected to be well over $100K.

Moe is currently at Dana-Farber and in the process of a bone marrow transfer due to the development of Myelodysplastic Syndrome, which can develop into acute myeloid leukemia. Moe has been with Dana-Farber for well over 5 years and been anxiously waiting for this day to come.

The Post-Office will provide him with 6-weeks of salary but after that will be down to Lauren’s teacher salary and Moe's social security. Moe’s recovery will continue on for a year at minimum which means he can’t work for well over a year and until he can get his second round of childhood vaccinations. In fact, he can not eat anything other than frozen food and food prepped by Lauren.

History of our Moe:

Moe was born with Shwachman-Diamond Syndrome named by two doctors Diamond and Shwachman. For the first year of his life he lived in the hospital malnourished not being able to digest fats from foods and neutropenic (low blood cells). It was literally the grace of God that my parents crossed paths with a very special doctor at Children’s Hospital in 1982, Dr. Diamond.

At an early age, he was given a very short life expectancy. With the strength and doctor-like qualities our parents provided him, he made it through each and every single night sick and deathly and lived a fairly “normal” childhood.

There is just so much leading up to this moment and I could go on and on with past health trauma and the struggle of living with a disease such. Please know that as family we all had the understanding and knew that this was going to be the outcome should he live past the expectation of this disease. Although frightening and all other imaginable emotions involved, we are just so excited that when the bone marrow begins to build and new cells develop that he will NEVER have to worry about this form of bone marrow failure again.

One other important piece to this journey is that Moe has been blessed with two donors and they are 10/10 matches, his sister Tiffany and brother Joey. They have both stepped up and said YES without hesitation. Tiffany was chosen and is already prepped and ready for intake. Her 3-hour procedure of removing healthy cells from her body and giving them to Moe will happen on July 27th.

We thank you all so much and just so blessed to have such amazing friends and family supporting Moe. From the bottoms of our heart and bone marrows, we thank you ❤️"

February 4, 2023

"Day +192: A lot has happened since our last update. Moe’s transplant was going well; attending weekly, then monthly doctors appointments. Experienced minor GVHD of gut, but overall was going smoothly. About 3 weeks ago, just shy of 6 months post transplant, Moe started having some trouble breathing. Just assumed it was some congestion/ cold, but no fever. After a couple days, we went to the ER because it wasn’t getting any better. They diagnosed him with organized pneumonia; unsure what caused it though. After 3 days, he was moved to the ICU because he needed more supportive oxygen. He started getting better after a week, however, they think he may have then aspirated into his lungs, making it worst. On January 23, they decided to intubate him and put him on a ventilator. He was not making much progress, however, was stable. Yesterday, after being on the ventilator for almost two weeks, they decided he needed a tracheostomy. Although slow, he has made slight progress this week. The doctor said it’s going to be a long difficult road, and will probably get worse before it gets better, but they are hopeful that he will make a recovery. We cannot thank everyone enough for your thoughts, prayers, and support. We are so fortunate to have such a strong community behind us. #MoeStrong #TeamMoe"

Moe passed away surrounded by his family on February 12, 2023. He was 41 years old.

Obituary

Maurice “Moe” Giordano III – Age 41, beloved husband of Lauren M. (Edie) Giordano died peacefully Sunday at the Brigham and Woman’s Hospital in Boston with his family at his side.

He was born in Lowell, April 14, 1981, a son of Michelle Granfield of Billerica and Maurice Giordano Jr. and Laura Giordano also of Billerica. He attended Billerica Schools and graduated from Billerica Memorial High School in 2000.

Moe was blessed with a large and loving family and spent a lot of time together. He married his high school sweetheart and have been together the last 24 years. He was a wonderful dad to his two cherished daughters; always attending their activities, father-daughter dances, and making them feel special. Moe was employed as a Mail Carrier for the U.S. Postal Service in Billerica for the past 22 years. He was so proud of working there and enjoyed seeing his post office friends and customers each day. Moe loved following sports, including the Patriots and Red Sox, collecting sport cards with his nephews, coin collecting with his brother, golfing with his friends, vacationing with his family, driving his Mustang Convertible, working in his yard, going to arcades & candy stores, watching movies, listening to country music, and playing with his dogs. He was always there whenever anyone needed a helping hand

Besides his wife and parents, Moe is survived by his daughters, Madison and Alexis Giordano of Billerica; his sisters, Melissa and her husband James Gaffney of Bedford, NH and Tiffany and her husband Michael Ostrander of Merrimack, NH; his brother, Joseph Giordano and fiancé Kerrianne Larson of Billerica; his maternal grandmother, Ruth O’Toole of Billerica, his mother and father-in-law Bob and Lorna Edie of Billerica, Brother and sister-in-law Shane and Tara Edie of Lunenburg, nieces and nephews James “JJ” and Stephen Gaffney, Joseph Giordano, Scarlette and Dominic Edie, and Andrew and Addison Ferola, and his fur babies Fenway, Jillette and Tuxy. He also leaves behind many aunts, uncles, cousins, and friends. He is predeceased by his maternal grandfathers Stephen O’Toole and Joseph Granfield, paternal grandparents Maurice Sr. and Cecile Giordano, and brother-in-law Robert Edie Jr.

Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

Unusual Shwachman-Diamond Syndrome case report of a 53-year-old woman in Uruguay, diagnosed in her 50s

We have known for a long time that Shwachman-Diamond Syndrome (SDS) presents differently in each patient. While most have blood and pancreatic issues at least intermittently, these hallmark signs are a not reliable tool for diagnosis. Before genetic confirmation became available about 20 years ago, patients were diagnosed based on symptoms alone. And SDS was almost never considered in adult patients, because it was assumed that they would have had obvious symptoms as children already, and because survival was assumed to be very poor. Now, genetic confirmation is routine and is allowing more and more adult patients to be diagnosed. Unfortunately, access to genetic testing is still a challenge, either due to a lack of knowledge or due to economic factors. We are working on both barriers to shorten the diagnostic odyssey for patients everywhere.

In the article we are highlighting this week, access to genetic testing has been a barrier, too. The authors describe the diagnostic journey and symptoms of a woman in her 50s in Uruguay. She has been followed by the clinic for 10 years and had many of the typical SDS symptoms (bone marrow failure with anemia and thrombocytopenia and neutropenia, cryptogenic liver cirrhosis, learning difficulties, short stature, bone issues, and dental problems, etc.), but she also had skin issues that are not typically seen in SDS (unusual skin pigmentation on her face, neck, and extremities; nail abnormalities; premature graying and thin hair). This lead the team to suspect telomeropathies (telomere biology disorders like Dyskeratosis Congenita) and pursued genetic testing specifically for that group of genetic disorders. The results turned out negative

Only later was it possible to pursue genetic testing for SDS using whole exome sequencing as part of a local pilot program aimed at promoting the use of sequencing for the diagnosis of rare genetic diseases. The test found two compound heterozygous mutations in the SBDS gene (the two most common mutations known in SBDS), which lead to the SDS diagnosis.

Unfortunately, the patient passed away in 2021 at the age of 53 years from sepsis due to severe neutropenia. She did not have AML.

“ The patient was followed in a pediatric hospital and referred to the adult hematology clinic which published this case report only at the age of 43 yr. The clinical presentation began during [...] childhood (because she had short stature, learning difficulties, delays in reaching developmental milestones as a child, and a history of cytopenias since childhood). This could have suggested SDS syndrome at that time, but because signs at pediatric age were nonspecific and the genetic tests were not easily available at that time in the country, the diagnosis ended up being very late. It might have been possible that having an early genetic diagnosis would have influenced our patient's outcome. “

We have reached out to the authors to offer assistance in accessing genetic testing, as well as educational and support resources for patients in Uruguay.

Two mutations in the SBDS gene reveal a diagnosis of Shwachman-Diamond syndrome in a patient with atypical symptoms.

Spangenberg MN, Grille S, Simoes C, Dell'Oca N, Boada M, Guillermo C, Raggio V, Spangenberg L. Cold Spring Harb Mol Case Stud. 2022 Dec 28;8(7):a006237. doi: 10.1101/mcs.a006237. Print 2022 Dec. PMID: 36577524

What exactly is Rare Disease, anyway?

Just in time for Rare Disease Day, or rather Rare Disease Month, let’s look at what Rare Disease actually means. Obviously, these are diseases that affect relatively few people. As a consequence, knowledge and treatment options are usually sparse.

To tackle a more clear and more consistent description of the concept of rare disease, the organization Rare Disease International (RDI) partnered with the World Health Organization (WHO) to come to a consensus.

In summary:

• A rare disease is a medical condition with a specific pattern of clinical signs, symptoms, and findings that affects fewer than or equal to 1 in 2000 persons living in any World Health Organisation-defined region* of the world. * WHO-defined regions are: Africa, Americas, Eastern Mediterranean, Europe, South-east Asia, Western Pacific
• Rare diseases include, but are not limited to, rare genetic diseases, rare cancers, rare infectious diseases, rare poisonings, rare immune-related diseases, rare idiopathic diseases, and rare undetermined conditions.

Talking about numbers….

“While the frequency of most rare diseases can be described by prevalence (the number of cases within a specific population at a given moment or over a specified period), some rare diseases, such as rare cancers and rare infectious diseases, can be more precisely described by incidence (the rate of new cases within a specific population over a particular period).”

Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

Expert consensus on the management of hematological complications in SDS by The European Society for Blood and Marrow Transplantation-Severe Aplastic Anaemia Working Party

A few months ago, the European Society for Blood and Marrow Transplantation-Severe Aplastic Anaemia Working Party published an expert consensus on the management of hematological complications in Shwachman-Diamond Syndrome patients. The study offers recommendations based on a thorough review of past publications and new data from Europe.

The key topics that the expert panel discussed and built consensus around were:

• Indications for Hematopoietic Stem Cell Transplantation (HSCT) - what is prompting the need for a transplant
• Hematological surveillance - how to determine the right timing for transplant
• Type of HSCT
  • Source of graft - how to select the donor for a transplant
  • intensity and type of conditioning regimen, and - what medication and protocol to use to prepare SDS patients for transplant
  • Graft versus Host Disease (GVHD) prophylaxis - how to prevent or reduce the risk of GVHD, one of the most dangerous possible complications during transplant

We reached out to the lead author, Dr. Simone Cesaro, to ask him to share a summary with our community. Here is what he shared with us:

Severe malignant and non-malignant haematological complications may occur in patients affected by Shwachman-Diamond syndrome (SDS) determining a risk for the life. Overall, 10-20% of Shwachman-Diamond patients may need hematopoietic stem cell transplantation (HSCT) in some point of their life to treat these life-threatening complications but, given the rarity of SDS, most transplant centres have a limited experience or different approaches. The European Society for Blood and Marrow Transplantation-Severe Aplastic Anaemia Working Party promoted an expert consensus to propose recommendations regarding key issues in the management of Shwachman-Diamond patients with hematological complications: indication to HSCT, modality to prepare the patient to transplant (conditioning regimen), choice of the donor, and prevention of graft versus host disease. The analysis of published data revealed some aspects that may be relevant for the optimal management and a successful outcome of the patient: a regular and structured haematologic follow-up is fundamental to identify early the timing of transplantation, avoiding, possibly, HSCT when the patient has already developed an overt acute leukemia or myelodisplastic syndrome. These last conditions have a lower benefit from HSCT. Moreover, the risk of severe toxicity related to the transplant procedure can be contained by using reduced-intensity conditioning regimens, or limiting the use of full dose of total body irradiation, particularly for transplant procedure performed for non-malignant severe cytopenia/bone marrow failure. On the other hand, the SDS patients whith a malignant complication represent a difficult to treat subgroup of hematological patients because the efficacy of chemotherapy is inferior than that observed in non-SDS patients, highlighting the need for innovative approaches in this setting.

The results are sobering. Once AML develops in SDS patients, the treatment options are very limited and outcomes are extremely poor.

So what can we do? Of course, it would be best if we could prevent progression to MDS and AML altogether. And that is why the focus of the SDS Alliance is centered around that. But in the meantime, we need to take advantage of existing cutting-edge technology to help our patients, now. One of the biggest unresolved issues is whether surveillance - the routine testing of the bone marrow (or blood) can help catch changes early enough before leukemia develops - to be able to intervene with a bone marrow or HSCT transplant. Early results by Dr. Shimamura (SDS registry) and others suggest so. Check out last week’s blog post on the subject. ,https://www.sdsalliance.org/post/sds-science-snapshots-2023-01-14

To make progress, we need large, carefully designed studies:

• We need to agree on what we think the best strategy for surveillance is (such as frequency of sampling, blood vs. marrow, agreed upon list of variants to test; and monitor how many many transformations are still missed.)
• Expand collaboration to as many international experts as possible.
• And very carefully assess whether a transplant provides a benefit, and in what specific situations (indication for transplant, graft availability, etc).

Transplant protocols have come a long way with better outcomes than they used to, but they are still very toxic and dangerous for SDS patients and a tool of last resort. We hope that targeting specific types of clones, or the bad cells specifically, will be possible someday.

,STEM CELL TRANSPLANTATION IN PATIENTS AFFECTED BY SHWACHMAN- DIAMOND SYNDROME: EXPERT CONSENSUS AND RECOMMENDATIONS FROM THE EBMT SEVERE APLASTIC ANAEMIA WORKING PARTY.

Cesaro S, Donadieu J, Cipolli M, Dalle JH, Styczynski J, Masetti R, Strahm B, Mauro M, Alseraihy A, Aljurf M, Dufour C, de Latour RP.

Transplant Cell Ther. 2022 Jul 20:S2666-6367(22)01472-5. doi: 10.1016/j.jtct.2022.07.010. Online ahead of print.

PMID: 35870777

Advances in newborn screening programs and the inclusion of Shwachman-Diamond Syndrome

One of the pillars of patient advocacy is striving to reduce and shorten the diagnostic odyssey. A faster and more accurate diagnosis means less suffering for patients and faster access to therapies and support.

Therapies and cures start with an accurate diagnosis - and that is another reason why we are working to increase the speed and access. Check out our blog post from last year for more details.

Today, we would like to draw your attention to newborn screening toward this goal. Newborn screening refers to public health programs in which infants are tested shortly after birth for a variety of conditions - traditionally conditions that are treatable, but not clinically evident in the newborn period. Read more on Wikipedia. These programs vary state by state, and country by country. We have looked into what it would take to get SDS covered in these traditional programs, and the hurdles and efforts necessary are insurmountable at this time.

Anyone who has a loved one with SDS knows instinctively that a faster and more accurate diagnosis would be priceless, even though we don’t have a cure (yet). Getting PERT (pancreatic enzyme replacement therapy) on board sooner to help our babies thrive is just one. Keeping an eye on the immune system and bone marrow, and initiating life-saving treatments in time, is another.

But there is good news on the horizon! Whole-exome sequencing (WES) based screening programs are being developed in many places. Some of them focus on babies who have obvious health issues and are in the NICU (neonatal intensive care unit). These programs are already showing that there is a huge benefit of these programs in reducing the time to diagnosis AND cost. Some other programs focus on expanding the traditional "standard" newborn screening (which covers only about 50 disorders) to use WES and cover thousands of disorders.

A pioneer in this field is Dr. Wendy Chung. She is spearheading the GUARDIAN study in NY to expand traditional “standard” newborn screening in the US to thousands of additional disorders.

Dr. Chung shared her insights and passion for the rare disease community in a new episode on the Once Upon A Gene podcast. If you haven’t subscribed yet, check it out. The podcast is hosted Effie Parks, the mother of a child with a rare disease. She highlights the unique experiences of parents raising children with disabilities and rare genetic disorders through conversations with remarkable parents, patient advocates, therapists, doctors and researchers.

We are so excited to share that we have connected with Dr. Chung to make sure that SDS is covered in the next edition of the GUARDIAN program. SDS will be covered in the new release of the study, available to new parents later this year! We will also work with her team to help spread the word and inform new families about the benefits of an early diagnosis, even for disorders that don’t have a “cure” yet. More on this and other outreach efforts coming soon!

Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on top right of this post:

Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

New comprehensive review article on the benefits and need for bone marrow surveillance in SDS patients

Fresh off the press, a new review article by Dr. Shimamura and Dr. Reilly was published on December 21, 2022, titled Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances.

This is a detailed review article that summarizes many of the key features and challenges in SDS, in particular the leukemia risk, bone marrow biopsies for monitoring, and transplant considerations.

As we all know, Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The article provides an overview of the pathobiology of SDS, which is a scientific term for the mechanism within the cell that causes the problems in SDS as a result of the mutations underlying SDS. SDS results from impaired ribosome maturation, i.e. the cell is not able to assemble as many ribosomes as it normally needs. We have created a video about this previously.

The article highlights that the outcomes for SDS patients who develop myeloid malignancies (i.e. acute myeloid leukemia, AML, a specific type of blood cancer) are still extremely poor. This is because SDS patients are highly sensitive to chemotherapy and also because this type of leukemia is a very hard to treat in general and often comes back even after a successful hematopoietic stem cell transplant (HSCT).

Data from the North American SDS Registry indicate that outcomes are improved for SDS patients who undergo routine bone marrow surveillance - i.e. bone marrow biopsy and aspiration and then examining the samples with several kinds of tests - and receive a HSCT prior to developing leukemia. This article sets the stage to evaluate what the optimal approach to hematologic surveillance and timing of HSCT for SDS patients may be, what to look for, and what types of testing are recommended.

The article also summarizes recent studies regarding the distinct patterns of somatic blood mutations in SDS patients that either alleviate the ribosome defect by somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints resulting in increased leukemogenic potential (heterozygous TP53 inactivation). This concept is complex but really important in SDS. If you would like to learn more, check out our video from 2021: ,Clones in SDS: The good, the bad, and the ugly.

The article presents and summarizes evidence supporting hematologic surveillance for SDS patients that incorporates clinical, pathologic, and molecular data to risk-stratify patients and prioritize transplant evaluation for SDS patients with high-risk features.

The field of clonal hematopoiesis - especially when it comes to genetic predisposition to malignancy such as SDS - is fairly new. We would like to thank Dr. Shimamura, Dr. Reilly, and Dr. Lindsley, for the groundbreaking work in this area and their efforts to provide these insights and spread awareness to the medical community. Looking into the future, we need the international hematology and SDS community to come together and develop a consensus on how SDS patients should be monitored, what genetic changes should be tested and what they mean, so that all patients - regardless of where they are - can be confident that they receive adequate care. We are ready to support the process.

Additionally, we are calling on all SDS patients to consider participating in the North American SDS Registry and all other clinical registries in their geographic area to support important work such as this. A list on clinical registries is available on our website, here: ,https://www.sdsalliance.org/sds-registries

The full-text article is currently behind a paywall, but the abstract is publicly available. Please reach out if you need access to the full text. [Update: as of summer 2023, the article is now available open access using the same links posted here]

Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances.

Reilly CR, Shimamura A. Blood. 2022 Dec 21:blood.2022017739.

doi: 10.1182/blood.2022017739. Online ahead of print. PMID: 36542827

Recap of ASH 2022

The 64th American Society of Hematology (ASH) Annual Meeting was held last month, from December 10-13 in New Orleans, Louisiana.

Dr. Hars, as a representative of the SDS Alliance Non-Profit Patient Advocacy Organization, have been awarded complimentary registration to the 2022 ASH Annual Meeting & Exhibition (a $1,500 value) as an appreciation of our organizations’ continued effort and dedication to the patients and the field of hematology. We would like to thank the organizers of ASH for this opportunity!

According to ASH, there are “typically, more than 5,000 scientific abstracts submitted each year, and more than 3,000 abstracts are accepted for oral and poster presentations through an extensive peer review process.” In fact, doing a quick search on the now publicly available abstracts’ page, we found close to 6,500.

Importantly, there are several abstracts, posters, and talks about SDS or relevant to it. Here is our brief overview.

Related to the review article features above in this week's snapshots article, Ashley Galvin - in collaboration with the North American SDS Registry - presented an oral and poster abstract titled: ,Outcomes of Hematologic Complications in Shwachman Diamond Syndrome: High Risk Features and Implications for Surveillance

"AML carries a poor prognosis for patients with SBDS mutations, so early referral for novel therapies should be considered. Marrow surveillance including morphology, cytogenetics, FISH, and somatic mutation analysis identified patients who developed HRF (High Risk Features). Survival was excellent for patients transplanted for HRF. Although SDS is rare and patient numbers are small, these data show that regular comprehensive marrow surveillance can identify HRF to inform the need for closer monitoring or transplant prior to progression to malignancy."

SDS was also covered in an Education Program session titled: What is New in Classical Bone Marrow Failure Syndromes? (focus on management)

Inherited bone marrow failure syndromes are a complex set of disorders characterized by single or multilineage cytopenias and elevated risk of hematopoietic and other malignancies. Patients may present with classic phenotypes, such as neutropenia in Shwachman-Diamond Syndrome, but the increased use of germline genetic testing and other diagnostics have led to a growing appreciation of a wide spectrum of IBMFS [inherited bone marrow failure syndromes] clinical phenotypes and ages at onset ranging from children to adults. This educational session explored the clinical manifestations, genetic etiologies, and new avenues for the management of severe congenital neutropenia [including Shwachman-Diamond Syndrome], Fanconi anemia, and telomere biology disorders.

• Dr. Jean Donadieu (Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris, Cedex, France and director of the French congenital neutropenia registry) discussed therapeutic options for severe congenital neutropenias (SCNs) beyond granulocyte colony stimulating factor (GCSF) and hematopoietic cell transplantation, using three different genetic disorders as examples. First, the talk described the rationale for the use of inhibitor of sodium glucose cotransporter (ISGTL2), an anti-diabetic drug, in glycogen-storage disease type-IB and glucose-6-phosphatase catalytic subunit-3 (G6PC3) neutropenias; Second, a potential role of C-X-C chemokine-receptor-4 inhibitors in warts, hypoglobulinemia, infections and myelokathexis (WHIM) syndrome. And third, it discussed the concept of stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation, like EIF6 inhibitors in Shwachman Diamond Syndrome - an area of focus in several research labs.
• Dr. Carlo Dufour (G.Gaslini Chidlren's Hospital, Genova, Italy) focused on management of Fanconi Anemia and its clinical complications starting with presenting a case report that outlines the importance of a long-term specific monitoring plan in this setting. The talk will outlined monitoring strategies tailored to timely detect hematological complications in order to perform hematopoietic cell transplantation (HCT) in optimal conditions. The most recently adopted HCT platforms was discussed. This talk also addressed surveillance approaches to identify early cancers, especially epithelial cancers of head and neck and urogenital regions, that currently have no satisfactory treatment.
• Dr. Sharon Savage (Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD) discussed the numerous genetic discoveries and the advent of clinical telomere length testing that have led to the recognition of a spectrum of telomere biology disorders (TBDs), beyond classic dyskeratosis congenita (DC). While hematopoietic cell transplantation and androgen therapy are effective for bone marrow failure in TBDs, there is a paucity of options for the other manifestations, such as pulmonary fibrosis, liver disease or cancer. This talk highlighted areas in need of additional clinical and basic science research while providing the background for clinical diagnosis and management.

Another way to look at SDS is by comparing it to other neutropenias caused by different genetic disorders. Dr. Maksim Klimiankou (Department of Hematology, Oncology, Clinical Immunology, University Hospital Tuebingen, Tuebingen, Germany) presented an oral and poster abstracts on this topic, titled: Accumulation of Specific Somatic Leukemia-Associated Mutations in Congenital Neutropenia Precedes Malignant Transformation – New Preconditions for Treatment Decisions

There were several abstracts submitted on model systems, namely three on zebrafish and one on mouse:

• Dr. Usua Oyarbide (Department of Cancer Biology, Cleveland Clinic, Cleveland, OH) presented an abstract titled: Deletion of eif6 Partially Rescues Survival, but Not Neutropenia, of Zebrafish Model of Shwachman-Diamond Syndrome: The Roles of Sbds and Eif6 in Perturbing Lipid Metabolism

  "We conclude that the organismal models of sbds or eif6 deletion provide new insights into the pathophysiology of human SDS: 1) SBDS affects lipid metabolism possibly due to an accumulation of EIF6, 2) Loss of eif6 affects development/survival at an earlier stage than loss of sbds, and 3) Loss of either sbds or eif6 markedly upregulates cdkn1a, which is downstream of tp53. Interestingly, Eif6 partially rescues survival of sbds-null organisms, but only in the haploinsufficient state. EIF6 may offer a promising target for a novel therapeutic strategy in SDS."

• Dr. Nozomu Kawashima (Cleveland Clinic Dept of Cancer Biology, Cleveland) presented an abstract titled Deletion of efl1 in Zebrafish Recapitulates the Spectrum of Shwachman-Diamond Syndrome

  "Zebrafish lacking efl1 phenocopied some of the molecular and morphologic features of SDS. Additionally, results from efl1-/- zebrafish were consistent with those from sbds-/- zebrafish strains, emphasizing a common molecular pathway induced by the dyad of EIF6 dissociating factors. Ongoing studies, which will be presented, are evaluating skeletal abnormalities and pancreatic atrophy in the efl1-/- zebrafish. Interestingly, sbds-null and efl1-null fish survived longer than eif6-null, suggesting more critical functions of EIF6. Altogether our data and presented elsewhere advance the hypothesis that CDKN1A and EIF6 contribute to the pathophysiology of SDS due to either mutations in SBDS or EFL1."

• Dr. Sarada Ketharnathan (CHEO Research Institute, Ottawa, ON, Canada) presented an abstract titled: A Zebrafish Model of Dnajc21 Deficiency Identifies Essential Roles in Granulocyte Differentiation and Metabolic Regulation

  "Our findings suggest that Dnajc21 is required for normal granulocyte differentiation and cell proliferation. We also identified previously unrecognized roles for Dnajc21 in regulating cellular metabolism. We propose that the zebrafish models described here readily serve as in vivo platforms to identify therapeutic compounds that restore normal hematopoiesis and prevent leukemic transformation in SDS."

• Dr. Michael Peters (Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA) presented an abstract titled Targeting a Putative Intronic Splicing Silencer Salvages Expression from the Recurrent SBDS C.258+2T>C Mutant Allele in Shwachman-Diamond Syndrome Patient Cells and Mouse Model

  "[..] Disruption of sequences within this putative ISS by Cas12a nuclease-mediated indels result in 1.4 and 2.4 fold increased SBDS/Sbds expression from SDS patient fibroblasts and homozygous MEFs respectively (p<0.05). Together these studies present a novel mouse model for SDS recapitulating the recurrent SS mutation with residual intact splicing and indicate that salvaging residual SBDS expression by modulating aberrant splicing is a promising strategy for SDS therapeutics."

We applaud all the researchers from around the world who work on SDS and bring us closer to therapies and cures. A heartfelt THANK YOU on behalf of the SDS Alliance and the patient community!

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One such effort is the SDS Cell Biobank, designed to enable researchers fast, easy, and affordable access to SDS patient-derived cells and cell lines – no matter where the researchers or patients are in the world. A biobank is a collection of biological samples (such as blood or cell lines derived from blood cells) and health information for research purposes. Up until now, there was no public biobank for SDS patient samples, and access to such samples was difficult and slow for researchers who are not affiliated with research institutions that see SDS patients regularly.

To address this critical need, we partnered with the ,Coriell Institute and launched a pilot program to bank and distribute Shwachman-Diamond Syndrome (SDS) patient-derived cell lines, globally.

The Coriell institute is an independent, non-profit biomedical research center dedicated to the study of the human genome, and features programs in biobanking, personalized medicine, cell biology, cytogenetics, genotyping, and induced pluripotent stem cell science. What is particularly exciting about this collaboration is not only their exceptional quality standard but their experience and focus on the distribution of samples.

The SDS Cell Biobank pilot program was a complete success. Patients can consent and submit their medical records and blood samples. The blood sample can be obtained as part of their routine care, without the need for an extra needle stick, using a kit and return shipping label provided by the Coriell Institute. The Coriell Institute processes the cells from the blood sample into a renewable cell line (see below), and adds it to their public catalog online, complete with all the de-identified relevant information about the sample. Researchers are now able to order the cells quickly and easily.

Our focus currently is on “renewable” cell lines. That is, patients, donate their sample only once, and Coriell creates cell lines that can be expanded and distributed indefinitely or to as many researchers as requested. As part of the pilot project, currently available products include, Lymphoblastoid Cell Lines (LCLs). Coming soon are Fibroblasts and iPSCs. The iPSCs are part of a separate project announced earlier, ,here.

We are happy to report that shortly after the first sample became available, researchers from both a pharmaceutical company and an academic institution ordered, received, and started using the SDS samples. None of them would have been able to access such samples easily otherwise, as they were not previously invested in the SDS community. Both have confirmed to us that without easy access to samples, they would not be able to evaluate whether their technologies have a possible benefit for SDS patients. With the samples, however, they can make a quick evaluation and consider developing larger programs to benefit our patients. More on these projects, soon. ~ Dr. Eszter Hars, President and CEO, SDS Alliance

Due to the success of this pilot program, we are planning to expand this effort starting early next year.

• If you are an SDS patient or a close family member and would like to participate, please email us at ,biobank@SDSAlliance.org. All patients and their parents and siblings are invited to donate a blood sample (and optionally a skin biopsy sample to bank fibroblasts). We can coordinate international donations as well.
• If you are a researcher interested in samples, please email us at ,biobank@SDSAlliance.org and we will connect you with any resources you may need. The samples at Coriell are available immediately. International shipping is available.

Thank you to all the patients who participated in the pilot, and the researchers who jumped at the opportunity to get involved in SDS research and therapy development. Together, we can create a bright future for SDS patients worldwide.

About the Coriell Institute and the NIGMS Human Genetic Cell Repository

The Coriell Institute for Medical Research is an independent, non-profit biomedical research center dedicated to the study of the human genome. Coriell features programs in biobanking, personalized medicine, cell biology, cytogenetics, genotyping, and induced pluripotent stem cell science. More information at ,www.coriell.org and ,Wikipedia.

The NIGMS Human Genetic Cell Repository, sponsored by the National Institute of General Medical Sciences, provides scientists around the world with resources for cell and genetic research. Established in 1972 at the Coriell Institute for Medical Research, the NIGMS Repository contains more than 11,800 cell lines, primarily fibroblasts and transformed lymphoblasts, and more than 5,900 DNA samples. Currently, the NIGMS HGCR catalog also contains over 85 iPSC lines.

Repository samples represent a variety of disease states, chromosomal abnormalities, apparently healthy individuals, and many distinct human populations. These samples comprise over 1,100 different OMIM diagnoses, and have been referenced in over 6,900 scientific publications. More information at www.coriell.org/1/NIGMS

Elijah grew up not knowing about SDS. Neither did his family. He developed health issues around age 23 including MDS. During the course of his treatment, he was diagnosed with SDS as the cause for his bone marrow issues. Later that year, he developed AML, and passed away from stem cell transplant and AML complications at the age of 25.

Thoughts from Elijah's mother, Erika.

Elijah left us Nov 30th. We’ve made it through one whole day without him physically here. I miss him. My heart hurts and yearns for him. To know him was a gift. That has become so very obvious as you have shared stories with us over the past few days. Thank you for those. Knowing those things is one thing, but reading and hearing new stories that confirm just how awesome we knew him to be is heart fuel for me right now. He had one of the most endearing souls.

When Elijah was born we said he was a wise old little yoda soul. It’s hard to explain but we just always knew he was different and special. I had him so very young, and although I had a full scholarship to pursue music, I knew in my heart I had to quit college to raise this tiny human, he was just too amazing to miss a thing. I am so glad I had the incredible honor to be his mom. He had a little Elmo voice and was the tiniest baby and kid in his class. But packed in that pint sized package was the biggest heart, filled with so much kindness, thoughtfulness, and courage.

Every teacher, coach or leader who ever taught him adored him, he was just that sweet. As Elijah grew, he held onto that gentle spirit. As other teens grew sassy he remained young at heart in so many ways. He was an encourager and was passionate about what he cared about. He loved fiercely from the start. While meek and humble in many ways, he was outgoing and full of humor and bravery when it mattered. He had many shirts that read ‘beast mode’. He was a whole lot of awesome packed into that seemingly quiet soul. He made people laugh and put them at ease or made them feel welcome…and always loved. He became a leader in whatever he was involved in, scouts and band were two of his youthful passions. But we were reminded of his ability to lead even in simple things like leading the the team of cousins on their beach scavenger hunt one summer vacation. People turned to him for guidance, comfort and strength. What a legacy.

And speaking of legacy, I am so grateful he knew love and not just with our immediate family but was able to find love and grow a family of his own. To be married and love wholeheartedly to his wife and have two insanely gorgeous children so young was a lot of hard work, but now we know he just had a lot of life to squeeze in… and that he did. & did it all out. He loved intensely and fiercely. His arrow pointed straight and true no matter what he was doing. Even in messiness, clumsiness, and mistakes, he owned what of those he needed to and picked himself up and did better every step forward in this life. What a legacy.

We do not mourn losing him because we know right where he is, but make no mistake we still mourn plenty. Thus far, God has given us what we needed when we needed it every step of the way. Impressive considering we had so much to tackle and coming at us for a year and a half… multi generational family dynamics, the overwhelming diagnosis journey and many healthcare decisions, the heartache and roller coaster of treatment and living out of state since May, navigating 3 separate lives and schedules so Elijah was never alone in Cincinnati. We are tired, we yearn for peace and rest but we still have work to do. We are planning an epic celebration of life for Elijah, because he was beyond epic. There is a go fund me being put in place because the best legacy we can put immediately into place for him now is financial security for his family.

There is so much to say and not enough paper or words or time. For now know we feel the love. We need the kind lifting words and support. We crave more time, hugs and conversations with Elijah but we will take stories of him and hugs with all of you for now. Thank you for loving us so well.

I think it’s no coincidence Elijah shared this exactly a year ago (November 28th, 2021) to the day we learned his hours and days were fading away. And then he swiftly went home to Jesus on Wednesday at Sunrise. He so desperately searched for his purpose for years, little did he know he’d been fulfilling it the whole time. He recently embraced his purpose was to inspire people during his journey this past year, if you knew him, you know he always has and always will. Case in point… the lyrics are incredibly profound today. …‘I won’t go to my grave, until a difference is made’.

Here are the lyrics in their entirety. I think they speak for themselves.

"Sunrise"

Full of despair inside a darkness

Self conscious and scared, held prisoner of war

Running out of air, buried in a sadness

Want a way out of this paralyzing world

And the sound of the cries when a family's loved one dies

It echoes through a vacant room where a young soul still resides

When the night is cold and you feel like no-one knows

what it's like to be the only one buried in this hole

You can make it to the sunrise.

(Woah. Woah. Woah)

You can make it to the sunrise.

(Woah. Woah. Woah.)

Searching for a way to escape the madness

A dire need for change as we fight for better days

The hurt and the pain cut deep like a razor blade

Holding in a cry for love, abandoned and afraid

When the night is cold and you feel like no-one knows

what it's like to be the only one buried in this hole

You can make it to the sunrise

(Woah. Woah. Woah)

You can make it to the sunrise

(Woah. Woah. Woah.)

I won't go to my grave until a difference is made

I won't go to my grave until a difference is made

(Until a difference is made)

When the night is cold and you feel like no-one knows

what it's like to be the only one buried in this hole

You can make it to the sunrise

(Woah. Woah. Woah)

You can make it to the sunrise

(Woah. Woah. Woah.)

I won't go to my grave until a difference is made

(Until a difference is made)

Until a difference is made

(From time to time, there arise among human beings,

people, who seem to exude love, as naturally as the sun gives out heat.)”

Thoughts from Elijah's father, Brian.

As I write this on the morning of November 29 2022, Elijah is still with us and is still fighting. Please share this with anyone or in any way that seems appropriate.

To be fully transparent, Elijah is more than likely in his last moments or days of life on this earth.

I have a very specific reason for writing this message today. As many of you know, I was privileged enough to spend a lot of time in Cincinnati with Elijah while he was in between hospital stays. We had a few amazing weeks while he grew stronger after his bone marrow transplant. We spent our time hanging out in the apartment in Bellevue Ky. We went into the hospital about every day for check ups and lab work. We tried to go on little adventures when we could, watch old movies, talk about life. I now find it very ironic that we spent this time in a little town that we would have never known otherwise. Bellevue. A name that means beautiful view. How appropriate since Elijah has shown us all a beautiful view of life. All of us.

One thing that Elijah made me promise to do was to gather the family and play this song for them. He said I would know the right time. I gathered our family last night. I gather all of you now. Elijah listened to this song over and over in Bellevue. This song rips my heart out but I know that it isn’t a song about death. It is a song about the next adventure. I am only able to have the strength to write this today because Elijah has a promise of one more adventure. A promise that so many of you have helped show and teach him about when he was young. Jesus is calling Elijah to another adventure. I think it is appropriate to share this with you while he is still here. He has asked a great task of me and I take it as the highest honor to share it with you now. If you are able, listen to this song. While I suspect you will offer prayers and comfort, do what Elijah would want……(always the little Boy Scout)… be prepared for your journey, at whatever time you are called to it.

To all strangers, friends, family. It is my honor to be the one asked to share this. From Elijah: “I bid you all, a very fond farewell”

I wrote a very long post last night that I think many people would find depressing. Myself, Erika Larsen Thompson and Jordan were in Elijah Thompson’s room laughing, telling stories and playing favorite songs. The post I wrote last night was about how I had to leave the room and listen to what has been my favorite song for the last year. Everybody hurts by REM. I had written about the roller coaster and what this song has meant to me. I went deep and shared more than I have shared with anyone. I decided I was not going to, or ready to share that so I deleted it.

As I sat in the hospital room this morning, I had the what I think might be the most amazing thing happen that only those in this circumstance may understand.

I love watching sunrises. To me, rain or shine, cloudy or clear sky, they are a beautiful promise of an uncertain day ahead. I have see amazing ones. I have been on a small journey to photograph a beautiful one. This morning, I sat at the foot of Elijah’s bed. I don’t write to share what was said. That belongs to Elijah and I alone. I write to say that as we talked. As I cried. As I looked over a hospital bed, monitors, more monitors. Looked across a city that is far from home. I looked across a foreground that no one ever wants to be in. But the background. The thing that lies out there waiting. The promise of things to come. That is what I write about this morning. As we talked, as if planned by God alone, I looked over all of this mess and I saw the most beautiful sunrise. Right on que. I almost grabbed my camera but then I thought, no, this one is mine. No one else gets to see this one. What you get from me today is a poor attempt at telling you this: Everybody hurts sometimes. Everybody cries. Hold on. Hold on to the things that you have faith in. Hold on to the ones you love. Ugly cry over the smallest of things. And then, sometimes, you get to see what I saw this morning in the childrens hospital in Cincinnati. You see the promise of better thing to come. You see God send a gentle little reminder that says yes, hold on. Hold on to this life while it is your gift but don’t lose sight of the promise of a new day. A beautiful future. A better gift.

Elijah, I so humbled and proud to be your father

October 31st

The dictionary can tell you what “roller coaster” means as a verb. Simply put, it is: move, change, or occur in a dramatically changeable manner. That is definition but how do you tell someone what it feels like…what it really is??

Any random day in the life of this crew could involve mom walking into a hospital and getting intercepted by one of the staff, some of whom become like family, to explain why 12 doctors are running in and out of the room like crazy. Dad going full send the last hour or so of an 8hr drive to hurry up and walk down that same hall and see someone outside the room talking to Erika and just wondering what each step is bringing me closer to. That same day brings the conversations about whether or not family needs to come up and the look from doctors that tells you to make it happen. Emergency plane tickets. Kassi, throwing a bag together and rushing out with two kids to the airport with no time to prepare. Jordan, agreeing to fly with Kassi before Erika can even finish asking him. That is one part of the ride.

Calling family members when you know you need to tell them something but you don’t know what to say. Hanging up on them and pretending to have simply lost signal just so you can yell and beat the hell out of something. (Sorry Laura Haas). More turns in the ride.

Having the absolute proudest moments as parents when you see a brother's love in action. To see Jordan take such good care of the kids and be with Elijah brings unbelievable joy to me. More ups.

Talks of power of attorney, DNRs, breathing tubes, all that goes along with that. Another twist on the ride no one wanted on in the first place.

Getting to spend an awesome afternoon in the park so Elijah and Kassi can have their time together. Abi refusing to use the park bathroom and Erika lugging her back to the apartment. Pushing swings until your arms are like spaghetti. Having a great day that, in a weird way, would not have happened without the twist in this ride bringing us here. Another corkscrew.

As I write this, I think about a literal roller coaster. You can imagine being placed on one maybe three or four cars back. You have someone beside you. A handful in front of you and more behind. You are insulted. You have a moment to see how those in front of you act and respond to the twist and turns. You kinda have the subconscious feeling that, the ones in front are ok and you will be too. Now imagine walking through the amusement park just to play some skee-ball and eat some cotton candy. Now you find yourself in the front seat of a coaster that has no defined path. A coaster that there is no one that has ridden this same one. No one ahead of you that you see taking the same twist before you do and coming out ok. You are in the front. You can’t see what is coming. You don’t see those behind you. In my head, that is what I imagine Elijah is going through. However, I feel like I get to see it from within and without (if you know, you know). I’m on the platform, I don’t see Elijah up front, alone on an empty coaster. I see him at the front of a line of cars that has anyone reading this, strapped in and buckled up. I see cars full of medical experts. I see a car full of hope, possibilities, dreams and prayers. I see a cars that are full of people who are there because God has placed each and every one of them there for Elijah and quite possibly for this very twist on the coaster. I see a car that has Elijah in the front and his family piled in right there behind him. We are right here with you T. We will hold you up and watch you through this the best we can. We’ve got you, the best we can. Now in my head, as I see all of this, I know that there is a reason this coaster is built with room for two at the front. The reason I say we are behind you Elijah is that I can’t experience what you have. I can’t take the tests, the biopsies, the chemo, arsenic, breathing treatments. I can’t be alone in a hospital room. I can’t see things from the perspective that only the first person in the cart sees. But, if I know anything in this world, I know this: this roller coaster might have you at the front and all of us behind but it does that because we are not strong enough. We are not who gets the front seat with you. We are on this ride, scared like you, enjoy the victories like you, questioning just like you, caught of guard just like you. That spot up front. The one that looks empty to some. The one that I, as your dad, can not fill. That spot is for the One that you chose years ago to place there. That spot has Jesus right there, right beside you, being what all of us can not. It is because of that, even if we don’t know what it is, this ride has a purpose and has hope.

Another twist. The first picture you see is all of us in the ICU a couple days after our big scare. That was taken right before Jordan and I brought the kids back to NC. Elijah is up, smiling, had a great visit and is back to making improvements. Definitely not out of the woods but is making daily strides in the right direction. In a couple days I will share a story about Elijah’s resiliency.

Life is like a roller coaster. It’s never going to be perfect - it’s going to have perfect moments, and then rough spots, but it’s all worth it. ~ Patti Smith

Thoughts from Elijah's wife, Kassi.

I don’t know where to begin, so I will begin with this. I never could have imagined life turning out this way. Elijah has been the most amazing husband I could have asked for. Even through this absolute valley we faced, our relationship only grew stronger. For that I am grateful. He was an incredible Husband, Father, Son, and Friend. Never have I met someone with such a kindness. More importantly, never have i met someone with such great faith. I’m writing this not for pity or for the “I’m sorry”s. I’m writing this because Elijah said he wanted people to know just how amazing God has been to him and the rest of us throughout this. He wanted to be an inspiration to all. Three days ago he made me promise that I wouldn’t stop telling his story, and that I would share all of the wonderful things that happened.

I’m not yet ready to relive every bit of the trauma from this past year, but I will say this. God provided. Every step of the way, God provided. He opened the doors, He gave the answers, He gave the resources, and most of all, He gave the peace to all of us. Philippians 4:19 says “And my God will meet all your needs according to the riches of his glory in Jesus Christ.” Elijah’s answer to any new challenges that he was faced with was always “God got me through before, and He will this time too.” And that statement couldn’t have been more true. God always, always, always provided.

2 Corinthians 9:8 “And God is able to bless you abundantly, so that in all things at all times, having all that you need, you will abound in every good work.”

Elijah has already been an inspiration to many, and I know will continue to be an inspiration. While Elijah‘s time here on earth is done, we are so happy that we know exactly where he is now. This isn’t goodbye, it’s simply see you later.

Psalms 34:10 “The lion may grow weak and hungry, but those who seek the Lord lack no good thing.”

Our hearts are hurting, but we are also overjoyed that he is now with God. I’m sure he opened those pearly gates Jedi style.

Note from the SDS Alliance:

• If you wish to support Elijah's family directly, donate to their GoFundMe campaign.
• To support the SDS Alliance's mission to #CureSDS in Elijah's memory, donate at www.SDSAlliance.org/Elijah.

On November 15th, Dr. Eszter Hars (SDS Alliance president and CEO) joined the FDA CBER OTAT Patient-Focused Drug Development Listening Meeting — Patient Perspectives on Gene Therapy Products meeting. We took the opportunity to highlight our community’s needs and perspectives, as several gene therapy projects are advancing - slowly but surely - towards the clinic.

"This meeting was our first step in working with the FDA to facilitate the evaluation of SDS therapies in the future to make them a reality." says Dr. Hars.

The meeting was hosted by the FDA’s Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) to better understand patient perspectives on gene therapy products, including cell-mediated gene therapies. This event was held to meet an FDA commitment that is part of the seventh authorization of the ,Prescription Drug User Fee Act (PDUFA VII).

“Patients and their advocates possess the unique, first-hand perspective of what it is like to live with or care for an individual with a disease, as well as the impact of available treatments on daily life. Patients and caregivers can provide valuable input into the discussion of investigational therapies by describing their experience with a disease or condition, and by defining meaningful change in terms of their specific disease and the risks they are willing to accept. With the potential for more gene therapies to become available to patients in the future, it is important to understand patient and caregiver perspectives on these products.” ~FDA CBER OTAT

The FDA is also collecting feedback and comments via written and electronic comments. These comments must be submitted by December 15, 2022.

For more information, visit ,https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/fda-cber-otat-patient-focused-drug-development-listening-meeting-patient-perspectives-gene-therapy

About the FDA

The United States Food and Drug Administration (FDA or USFDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), cosmetics, animal foods & feed[3] and veterinary products. (See more at FDA.gov and on wikipedia here: https://en.wikipedia.org/wiki/Food_and_Drug_Administration)

About OTAT

OTAT (a part of the FDA) oversees development for a wide variety of biological products, including gene and cell therapies, tissues and tissue engineering products, xenogeneic products, and more. OTAT strives to lead all regulatory decisions with data, impartiality, and compassion and always welcomes the participation of patients and their advocates in formal meetings related to the development of investigational products. Learn more about ,OTAT and view our available resources.

• When? October 8-15th, 2022
• Where? Virtual! Run/Walk/Roll wherever you like!
• What? Fun!!! Fundraise and Run/Walk/Roll in your community!
• Why? To build community and raise funds for SDS research!
• How? Registration is now closed, but you can still donate, ,here!

Here are some highlights the fundraising families shared. The new T-shirts - customizable with TEAM NAMES, were a big hit, too.

And just like that, it's a wrap. The conclusion of the 6-day long challenge: THREE MILLION STEPS CLOSER TO #CURESDS is worth celebrating. You stepped up big time and logged - drumroll please! - 3.5 MILLION STEPS! With your support, we have also exceeded the fundraising goal of $12,000 for this fundraiser.

A huge thank you to all who joined the SDS Alliance's third annual fun run challenge fundraiser and turned hope into action and took steps to #CureSDS - by walking, running, crawling, rolling, or leaning back and supporting those who did by making a donation.

You invited your family, friends, and neighbors to participate, raise awareness, and funds!

As always, 100% of funds raised from the community go to SDS research accelerating therapies, with no overhead! This year, our focus is on expanding the toolbox for SDS research and seed funding research in new therapeutic areas as part of our roadmap. We depend your support to drive the progress!

Three million steps are certainly too much for any single person. But together, the steps add up. Together, we did it!

And the winners of the challenges are:

Winner of the team challenge:

Winners of the individual challenges:

Here is what he shared with us:

"It was an honor to participate in such a motivating event, every opportunity to bring awareness to SDS is a worthy cause. God bless all of you battling SDS and every family affected by it!" ~ John

And in the women's category:

Here is what she shared with us:

"As the director of The Opportunity Preschool, I walked to support Kayla, Nora and their families along with the other children who are desperately seeking a treatment or cure for SDS. Together we can make a difference in helping people become more aware of this rare disease." ~ Linda

And last but not least, some more memories from last year.

Can't wait 'till next fall for the next installment!

Shwachman-Diamond Syndrome (SDS) fits into several different categories of disease. Most importantly, it is a cancer predisposition disorder – causing heritable blood cancers. Accurate and timely diagnosis is critical not only for better outcomes for patients with the treatment options available today but also for research and therapy development tomorrow. The learnings and therapeutic advances can impact a wide range of cancers beyond those related to SDS. Our focus here at the SDS Alliance is to drive therapy development toward eliminating the leukemia risk in SDS, or in other words, cancer prevention. In the meeting with the White House Cancer Moonshot team, we highlighted and emphasized these shared goals.

The HCPC is comprised of leaders from the ,Runx-1 Research Project (RRP), the ,Shwachman-Diamond Syndrome Alliance and ,Team Telomere - rare disease groups united by a shared goal of improving the detection and treatment of heritable blood cancers for their respective patient communities.

HCPC members – including Dr. Eszter Hars of the Shwachman-Diamond Syndrome Alliance – and Cancer Moonshot officials met on Friday, September 30th to discuss partnering on their similar goal of improving cancer detection and treatment, as well as enabling new cancer prevention strategies for blood cancers. As experts in this field, HCPC members offered to be a resource to the White House Cancer Moonshot 2.0 leadership team and to support its efforts to make meaningful progress against cancer.

We are all in agreement that leveraging precision medicine to enhance screening, customize treatments and enable the discovery of cancer prevention interventions are critical toward improved cancer survivorship and quality of life. We also highlighted the crucial role genetic testing plays in the early detection and prevention of heritable blood cancers in the general population. In addition to compelling statistics, we took the opportunity to share personal stories from our communities to drive the urgency home.

Dr. Catharine Young from the White House shared her commitment to meeting with the coalition again to establish actionable steps towards the goals discussed.

Stay tuned for updates!

Partnering with the ODC and the Coriell Institute will ensure that the iPSCs are the

• highest quality
• biobanking and storage are managed professionally
• distribution of the cells is fast and efficient, globally

The first phase of the project is set to start this fall, and the iPSCs are expected to be available to researchers – anywhere in the world – as soon as mid-2023.

Your donations to our “Expand the Toolbox” fundraising campaign made this project possible, turning hope into action. With the JumpStart Grant, we were able to leverage your donations three fold!

In the second phase of this project, we will further amplify the impact of the iPSCs by creating isogenic pairs. When researchers are testing therapeutics on cells, they need to prove that the effect they see is directly related to SDS (i.e. SBDS mutations), and is not just a random effect. The best way to show this is to treat two cell lines in parallel - one that harbors SDS mutations, and one doesn’t (but is otherwise all the same). If the effect is SDS specific, it should be much stronger in the SDS cells. To create the isogenic pairs, we will contract leading SDS and iPSC experts. Details to follow. But we need your financial support to fund this work and to leverage additional funding sources. Let’s turn hope into action and “Expand the SDS Research Toolbox” together.

This project is part of our roadmap. With your support, we are making steady progress every day.

We are excited to provide an update about the progress of the Mouse Model Project!

To recap, we launched this project last summer to fill a critical gap in the research toolbox: A mouse model that contains the exact mutation that over 90% of SDS patients have, with the hope that they will be viable and/or show relevant symptoms researchers can measure when evaluating the efficacy of new therapies and cures.

Please check out the two previous posts for background and details:

,https://www.sdsalliance.org/post/sds-mouse-launch

,https://www.sdsalliance.org/post/mouse-model-meet-the-scientists (with video!)

We are happy to report that Jackson Laboratory has completed the first phase of the project. They have created mice in which a large segment of the mouse version of the SBDS gene is replaced by the human sequence, including the human SBDS splice site mutation (aka the 258+2T>C mutation) that is responsible for SDS in the vast majority of SDS patients!

The research team is now entering into the next phase of the project, which is to characterize the gene expression (i.e. how does the humanized gene behave in the mouse) and evaluate viability and symptoms. Additionally, the team is exploring various genetic backgrounds to modulate disease severity.

While this work is ongoing, we are tirelessly working on further ,expanding the toolbox for SDS research with additional types of disease models and more. Before new therapies can be tested on real life human patients, researchers have to first show that it works in several types of disease models and is safe. In addition to animal models (typically mouse models), patient-derived cells (in a petri dish) are another critical tool to test and demonstrate that the therapy is likely to work in real patients.

Therefore, we are launching a biobank for patient-derived cells to be available to researchers anywhere in the world, quickly, easily, and cost effectively. More details and information on how to participate – or order cell lines if you are a researcher – are coming very soon. In the meantime, please email us at ,biobank@SDSAlliance.org for more information.

Welcome to our weekly updates on all things SDS, science, and advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

What is Congenital Exocrine Pancreatic Insufficiency?

Congenital simply means a health issue "present at birth". Exocrine Pancreatic Insufficiency (EPI) means that the pancreas doesn't produce enough digestive enzymes. This video explains the function of the pancreas in great detail, including the difference between exocrine and endocrine functions.

EPI - especially in children or in the absence of any obvious reason like pancreatitis - is often due to a heritable condition, such as Cystic Fibrosis (CF) or Shwachman-Diamond Syndrome (SDS). Many SDS patients have heard about CF as part of their diagnostic journey, especially if EPI was one of the first major symptom noted. In many cases, healthcare providers want to rule out CF first using the so-called sweat test, before proceeding with genetic testing for SDS. These two diseases are completely unrelated to each other, each being caused by mutations in different genes, and causing different health issues. The ONLY common feature is EPI. SDS is the second most common cause of EPI after CF.

If you need support with the treatment of EPI, usually Pancreatic Enzyme Replacement Therapy (medication under various brands such as Pertyze, Creon, Zenpep), talk to your doctor. We have some helpful resources on our website, here, including financial assistance programs.

Last week, Drs. Scheers and Berardis from Belgium published a review article summarizing the mechanism of several congenital EPIs, including CF and SDS.

Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation.

The article includes a nice visual overview

Congenital etiologies of exocrine pancreatic insufficiency. Scheers I, Berardis S. Front Pediatr. 2022 Jul 22;10:909925. doi: 10.3389/fped.2022.909925. eCollection 2022. PMID: 35935370 Free PMC article. Review.

Can genetic disorders be treated in the womb?

For many genetic disorders, it would be a dream come true to be able to treat the disease in the womb, before the mutation can cause irreversible harm. There is a lot of active research happening trying to apply gene therapy approaches in the womb, but we are not quite there yet. A great example is highlighted in this article from a few years ago.

But gene therapy may not be the only way. What if drugs could get to the fetus and start working before the baby was born? What if any of the current therapy development efforts for SDS succeed and the therapies could be applied in the womb already so that SDS complications could be reduced to a minimum?

Since we were talking about CF above, I wanted to highlight a recent case report on CF suggesting that this could possibly work. The authors report the treatment of a mother who is a CF carrier with a combination drug (ETI) treatment commonly used for CF patients. The fetus was suspected to have CF at 23 weeks gestation, due to several typical features of CF.

Through shared decision-making, the mother began ETI at 32 weeks with intent to treat fetal MI [CF symptom]. The ultrasound findings persisted at treatment day 13, but bowel dilation had resolved by imaging on treatment day 27. A female infant was delivered vaginally at 36 weeks with no complications. The mother continued ETI while breastfeeding. Stool elastase at age 2 weeks was 240 mcg/g. Sweat chloride measurement was 64 and 62 mEq/L. Maternal and infant liver function testing have been normal. Maternal ETI treatment likely led to resolution of the MI and there is evidence supporting continued infant benefit through breastmilk. Logistical and ethical considerations regarding treatment of a carrier mother for infant benefit are discussed.

See the original article here:

A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus.

Szentpetery S, Foil K, Hendrix S, Gray S, Mingora C, Head B, Johnson D, Flume PA.J Cyst Fibros.

2022 Jul;21(4):721-724.

doi: 10.1016/j.jcf.2022.04.005. Epub 2022 Apr 11.PMID: 35422395

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Steve, Niamh's beloved husband, shares Niamh's story.

On Thursday 11th August 2022, our world changed forever. This is the day our beloved Niamh passed away from a short illness caused by a bacterial infection which proved tragically fatal. On the Tuesday of that week she was in great form, we'd been out on a sunny day enjoying a few drinks in a beer garden and nice Chinese meal. On the Wednesday she fell ill and we took her to hospital, by the Thursday she had left us.

The infection was called necrotising fasciitis, its a rare but dangerous bacterial infection. Niamh had chronic neutropenia which meant she was more likely to catch this, and sadly less able to fight it due to having a very weak immune system. Niamh had only found out within a year before she passed away of her diagnosis of SDS, which led to her neutropenia condition.

Niamh actually took comfort and encouragement from her SDS diagnosis, it helped explain some of why she had suffered since a baby, she felt a new additional support from the online SDS community, and it gave her hope to find a way to live a more healthy life through leaning more about the condition. Cruelly ironic, we had an appointment with her consultant to learn more about SDS on the day she died.

Niamh was in and out of hospital as a baby, regularly sick throughout her childhood, and barely a month went by as an adult without seeing one of her numerous medical consultants for the several conditions she was living with. Sadly this is the reality of living with SDS. She also suffered significant loss emotionally, in particular her beloved mother Mary passed away whilst Niamh was still in her teens.

But despite all of this, Niamh was the loveliest, bubbliest, most cheerful, caring, generous and silliest person you could ever have the fortune to meet.

Anyone that knew her said she would light up a room when she entered. Born and bred in Dublin, Ireland, she came from a large & loving Irish family, and she was extremely close to all from the close & extended family.

She also made huge efforts to always spend time with her many friends, she was loyal and great company to all. A special mention to her best friend Karen, they knew each other since school and were like sisters, supporting each other through good times and bad.

Niamh was well known in her community, since we moved into the neighbourhood 10 years ago she set upon herself to organise the first ever street party here (and also the 2nd and 3rd!) before covid put a halt on those. As a stop gap she dragged her karaoke machine onto the road and we played socially distanced bingo to keep everyone entertained through difficult isolating times. And she never stopped trying to get involved with local people and getting people together, no better shown than when within the year before she died she founded the Dublin 7 Women's Shed, which is now going from strength to strength with well over 100 members.

Some of Niamh's very best friends though did not have 2 legs but 4. She was a lover of all animals, and in particular dogs. Whilst not working during covid Niamh minded several local dogs on a part time basis and took great joy out of this, as did all the doggies! And whilst we never had children, we did have our own little dog Basil, a Cavalier King Charles. Sadly Basil passed away 2 weeks after Niamh, he was 14 years old, and just as heart broken as everybody else, he loved his mammy very much.

I met Niamh backpacking around New Zealand in 2006. Niamh loved a holiday whether it was exploring a new place, travelling round beautiful Ireland with Basil, or soaking up some rays in the sun. She said her favourite trip was when we went to Cuba, we did this on a group tour and typical of Niamh, she was the life and soul of the group and quickly nicknamed the Daiquiri Queen.

Niamh loved to be busy when she was able, and also loved the outdoors, so her recent taking up of gardening suited her well. Her specialities were growing of spuds, tomatoes, sweetpea and sunflowers. Niamh loved to laugh, whether it be cheesy puns or sticking googly eyes everywhere. We'd regularly attend comedy gigs together. She had a daft and silly sense of humour, her giggle, often starting as a cackle and sometimes becoming so unstoppable that it almost caused her to choke and quickly grab her inhaler, was unique, unmissable and infectious, and full of joy.

Niamh loved music and going to gigs, especially outdoor festivals. She always had a fun loving 60s/70s vibe and would have fit in well when the Beatles and Donovan were banging out the tunes. She could dance around to cheesy pop, and head-bang to something more rocky and punky. Her favourite band were Ash, and their song Shining Light we've since adopted as its such a beautiful description of Niamh, our shining light.

Another band we got into recently are called Dream Wife. And that for me is the perfect description of Niamh. She was loving and caring. She was supportive and understanding. She was smart and funny. She was brave and courageous. She was great fun, the best craic you can imagine. She was beautiful from head to toe. She was my best friend and my soul mate.

Life is unbelievable tough now without Niamh by our side. She was loved by so many, and we were all lucky to be loved by Niamh. Niamh was always one who saw the best of people and the positives in situations wherever they existed. So in that vain, along with some close family and friends, we'll be participating in a remembrance run this November, doing this both in Niamh's memory and also to raise funds for the SDS Alliance.

• https://www.dublinlive.ie/news/dublin-news/my-wife-died-rare-disease-27714675
• https://www.gofundme.com/f/in-memory-of-niamh-curesds

Niamh Lynch-Livsey, aged 44 years, forever young, always loved, always in our hearts.

Welcome to our weekly updates on all things SDS, science, and advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

What is a protein 3D structure and why it matters

Biological processes in both health and disease are mostly mediated by proteins in our cells. Proteins are long chains of amino acids (the building blocks) that fold up into specific 3D structures. This structure along with their chemical properties on the surface is responsible for the proteins' function. The exact sequence of the amino acids is determined by the nucleotide sequence encoded in our DNA. Each gene - a defined stretch of DNA - encodes one protein. As you can imagine, if there is a mutation in a gene, it can result in a change in the amino acid sequence - which in turn can change or disrupt the resulting protein structure and function.

Here is a great overview on how the 3D structure of a protein comes to be:

Plus, a handy overview of how amino acid chains fold into 3D protein structures:

And what does this all have to do with Shwachman-Diamond Syndrome?

Shwachman-Diamond Syndrome (SDS) is an inherited (aka genetic) disorder that is (in over 90% of patients) a result of mutations in the SBDS gene. When mutated, the SBDS gene gives rise to either not enough SBDS protein, or an SBDS protein that has lost its function. The SBDS protein is responsible for catalyzing the assembly of ribosomes. If there is not enough SBDS protein, then there is not enough ribosome, and the cell is not able to keep up with overall protein production.

We created a video overview on this topic, here:

SBDS structure and why it is important as a therapeutic target for SDS

Since SBDS takes center stage in Shwachman-Diamond Syndrome, it is not a surprise that understanding the details of its function and what it looks like in 3D is critical when it comes to developing strategies for therapies and cures.

Dr. Alan Warren has championed this effort for many years since the SBDS gene was identified to be the main cause of SDS by Dr. Johanna Rommens' group in 2003. In this recent video interview, Dr. Warren explains the importance of a thorough analysis of the structure and how these insights feed into small molecule drug development - championed in his lab. Read his detailed article about SBDS and SDS from 2018, here.

New article on SBDS structure and dynamics

In this new article published this month by Dr. Mangiatordi's group in Italy, the authors report their work using comparative Molecular Dynamics simulations to analyze the impact of three different point mutations in SBDS on the protein function. The results indicate that both the open and closed forms of wild type SBDS are necessary for proper SBDS function, and support the hypothesis that SBDS function is governed by an allosteric mechanism involving domains I and III.

Read the full article (open access), here:

A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman-Bodian-Diamond Syndrome Protein SBDS.

Spinetti E, Delre P, Saviano M, Siliqi D, Lattanzi G, Mangiatordi GF. Int J Mol Sci. 2022 Jul 19;23(14):7938.

doi: 10.3390/ijms23147938. PMID: 35887285

On the news: DeepMind's protein-folding AI cracks biology's biggest problem

Coincidentally with our theme "protein structure" in this issue, there was big news in the science world this week. Google’s AI outfit and the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI) announced Thursday that DeepMind’s AlphaFold database now contains the structures of more than 200 million proteins. It’s a substantial jump from where it was a year ago when DeepMind announced that it had predicted the structure of only about 350,000 proteins.

The two companies said in a statement announcing the database expansion that it now contains the structure of essentially every protein that has been sequenced — and is designed to function essentially like a Google search. On top of that, the companies are keeping it free for use for the scientific community at large.

Understanding protein structure is an overarching challenge in research and therapeutic development. Learning about structure can teach us about disease mechanisms and creating effective treatments - including for Shwachman-Diamond Syndrome as we discussed above. But as you can see, this process is anything but trivial. Long sequences of amino acids can take on many shapes and structures (conformations), which can change as they bind with other proteins or ligands, or through changes in their environment.

The gold standard for "looking at" protein structure is X-ray crystallography - a complex and resource intensive technology that is hard to scale. That's where Artificial Intelligence (AI) comes in. To accelerate our understanding of protein structures, DeepMind has developed AlphaFold, an AI approach that predicts protein structure based on existing observations of the protein and some basic rules about protein folding. DeepMind is now publishing the predicted structures of over 200 million proteins.

These predictions aren’t perfect: AlphaFold doesn’t always predict structural changes in response to a mutation, for example. But by providing likely structures of so many proteins, this technology has the potential to significantly accelerate molecular research of proteins in health and disease.

DeepMind has predicted the structure of almost every protein so far catalogued by science, cracking one of the grand challenges of biology in just 18 months thanks to an artificial intelligence called AlphaFold. Researchers say that the work has already led to advances in combating malaria, antibiotic resistance and plastic waste, and could speed up the discovery of new drugs.

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Welcome to our weekly updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email ,connect@SDSAlliance.org or message us on Facebook! This is all for you!

What is neutropenia and how does it happen in SDS

Neutropenia simply means that a person's blood doesn't have as many neutrophils - a type of white blood cells - as it should. This puts the person at risk for bacterial (and other) infections. A large percentage of Shwachman-Diamond Syndrome (SDS) patients have neutropenia, at least for a period of time. The type of neutropenia that is caused by SDS is considered Congenital Neutropenia, because it is caused by a gene defect and can be present starting at birth without any other cause.

A few weeks ago, we had the pleasure to attend a lecture by Prof. Dr. Leo Koenderman,

Department of Respiratory Medicine and Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands, organized by Dr. Valentino Bezzerri, PhD, Principal Investigator, Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata di Verona, Italy, as part of the Young-EuNet-INNOCHRON online discussion series.

Dr. Koenderman explained the mechanism of neutrophil homeostasis - the process by which the body typically regulates how many neutrophils are circulating in the blood stream vs. stored in the the bone marrow. Over the past decade, a lot of the text book information has been updated regarding this process.

For a deep-dive into the topic, check out these PubMed references:

• Kinetics of Neutrophil Subsets in Acute, Subacute, and Chronic Inflammation
• The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination
• The Neutrophil Life Cycle
• What's your age again? Determination of human neutrophil half-lives revisited

For a general overview on how neutrophils are produced in the bone marrow and how they work is available in these two videos:

Study highlights the multibillion dollar burden of rare disease

Annie Kennedy, chief of policy, advocacy, and patient engagement at the EveryLife Foundation for Rare Diseases, tells PharmaPhorum about why the Foundation sponsored The National Economic Burden of Rare Disease Study, undertaking the challenge of examining the financial impacts of rare diseases.

"Our primary focus is ensuring we can work to eliminate barriers and identify challenges to therapeutic development for rare diseases,” Kennedy states.

Before the study, the Foundation had a large amount of anecdotal evidence or estimates regarding the financial burden of rare diseases. This study aimed to garner objective evidence of the economic burden of rare diseases by working with the broader rare disease community.

Health touches all facets of our lives. The cost of a disease goes way beyond what is billed to insurance for doctors, hospital visits, and prescriptions. These indirect costs include lost productivity and caregiver investment and are often underestimated, especially for rare diseases that aren’t codified in our medical systems. An accurate idea of this financial burden is necessary to establish more adequate care systems and priorities.

The EveryLife Foundation created a survey of 1,400 rare disease patients, comparing their 2019 expenses to documented direct healthcare costs. They quantified something that most families with rare diseases — including SDS families — already experience first hand. More than half of expenses were indirect and covered by the family.

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Bienvenue dans nos mises à jour hebdomadaires sur tout ce qui concerne la SDS, la science et le plaidoyer. Nous vous apportons un résumé des publications scientifiques récentes, des conférences et d'autres contenus dignes d'intérêt - tous pertinents pour SDS - avec des liens vers plus de détails et des opportunités d'apprentissage. Êtes-vous intéressé par quelque chose de spécifique? Avons-nous raté quelque chose ? Faites le nous savoir. Envoyez un courriel à connect@SDSAlliance.org ou envoyez-nous un message sur Facebook! C'est tout pour vous!

CRISPR-Cas9 fête ses 10 ans

CRISPR a fait ses débuts il y a 10 ans, dans un article que presque personne n'a remarqué: en juin 2012, un communiqué de presse conjoint a été publié par le Département américain de l'énergie et le Laboratoire national Lawrence de Berkeley annonçant un nouvel article dans Science «Programmable DNA Scissors Found for Bacterial Immune System».

Dans ce document, les auteurs ont souligné que la découverte pourrait conduire à un nouvel "outil d'édition des génomes". Le document a maintenant été cité par plus de 15 000 publications et téléchargé près de 65 000 fois. Dans ce document, les désormais célèbres auteurs lauréats du prix Nobel - Jennifer Doudna et Emmanuelle Charpentier - ont expliqué le fonctionnement interne d'un système appelé CRISPR/Cas9.

Bien que l'impact incroyable n'ait pas été immédiatement reconnu par le public, une décennie plus tard, il n'y a presque personne qui n'a pas entendu le terme. CRISPR a été utilisé pour manipuler les génomes d'organismes dans toutes les branches de l'arbre de la vie, y compris les humains. Il est actuellement testé pour traiter des dizaines de maladies héréditaires - dont de nombreuses maladies rares -, les entreprises prévoyant de demander aux régulateurs l'approbation du premier médicament basé sur CRISPR dès la fin de cette année.

Lisez un article de STAT sur leur entretien avec le Dr Doudna à l'Université de Californie à Berkeley, où elle dirige l'Innovative Genomics Institute.

Alors, qu'est-ce que la technologie CRISPR-CAS9 exactement?

En bref, selon le NIH-NCI, il s'agit d'un outil de laboratoire utilisé pour modifier ou "éditer" des morceaux d'ADN d'une cellule. CRISPR-Cas9 utilise une molécule d'ARN spécialement conçue pour guider une enzyme appelée Cas9 vers une séquence spécifique d'ADN. Cas9 coupe ensuite les brins d'ADN à ce stade et enlève un petit morceau, provoquant un vide dans l'ADN où un nouveau morceau d'ADN peut être ajouté. CRISPR-Cas9 est une percée scientifique qui aura des utilisations importantes dans de nombreux types de recherche. Dans la recherche sur le cancer, il peut être utile de comprendre comment le cancer se forme et réagit au traitement, ainsi que de nouvelles façons de le diagnostiquer, de le traiter et de le prévenir.

Regardez cet excellent aperçu de TED-Ed. Nous en avons également ajouté d'autres sur notre page "Comprendre la science SDS".

Vous voulez en savoir plus ? Découvrez cette ressource incroyable de l'Institut de génomique innovante, ici.

La promesse de la thérapie génique pour les maladies rares et le syndrome de Shwachman-Diamond (SDS)

La majorité des plus de 10 000 maladies rares sont de nature génétique, ce qui signifie qu'il existe une "faute de frappe" ou un changement dans la séquence d'un gène nécessaire au bon fonctionnement du corps humain. Si nous pouvions corriger le défaut spécifique du génome, dans les bons organes ou tissus, nous serions en mesure de fournir des remèdes aux millions de personnes souffrant de maladies rares. Le syndrome de Shwachman-Diamond (SDS) entre également dans cette catégorie. De nombreux facteurs font de SDS une cible fantastique pour l'édition de gènes. Il s'agit d'une maladie à un seul gène - causée par une mutation d'un seul gène - et la mutation particulière (ou "faute de frappe") est très uniforme. Plus précisément, plus de 90% des personnes atteintes de SDS ont des mutations dans un gène appelé SBDS, et presque tous ces patients ont au moins une "mutation du site d'épissage" (258 + 2T> C). Un autre aspect qui fait du SDS un excellent modèle de maladie est l'organe cible qu'il faudrait atteindre : la moelle osseuse. La moelle osseuse est beaucoup plus facile à atteindre que le cerveau, par exemple. La technologie d'édition de gènes ex vivo est réalisable : les cellules souches hématopoïétiques peuvent être obtenues de patients de la même manière que les gens donnent des cellules souches pour une greffe. Une fois récoltées, les cellules peuvent être "modifiées" - la mutation fixée. Ensuite, les cellules "fixées" peuvent être réinfusées aux patients, comme lors d'une greffe de cellules souches traditionnelle.

Bien sûr, tout cela est plus facile à dire qu'à faire, et de nombreux efforts de recherche nous attendent. La bonne nouvelle est que tout un laboratoire de recherche sous la direction du Dr Brendel au Boston Children's Hospital est dédié à ce travail. Ils se concentrent sur le développement d'approches pour personnaliser la machine CRISPR-Cas9 afin d'éditer efficacement les SDS les plus courants provoquant des mutations dans le SBDS. Ce travail n'en est encore qu'à ses débuts et il est probable qu'il reste des années avant qu'il n'atteigne les patients, mais il s'agit certainement d'une approche que nous devons explorer. Nous fournirons bientôt plus de détails et d'idées. Nous nous engageons à soutenir ce travail de toutes les manières possibles. En particulier, notre projet de modèle de souris cherche à fournir un outil essentiel pour accélérer ce travail, car il héberge la séquence humaine exacte qui doit être ciblée par CRISPR-Cas9.

Le Dr Brendel a récemment publié un article de synthèse soulignant comment et pourquoi "Les souris humanisées sont des outils précieux pour l'évaluation des thérapies géniques hématopoïétiques et la modélisation préclinique pour aller vers un essai clinique".

"Les contributions les plus importantes apportées par ces souris humanisées sont l'identification des cellules souches hématopoïétiques normales et leucémiques, la caractérisation de la hiérarchie hématopoïétique humaine, le dépistage des thérapies anticancéreuses et leur utilisation comme modèles précliniques pour les applications de thérapie génique. Cet article de synthèse se concentre sur plusieurs applications de thérapie génique qui ont bénéficié d'une évaluation chez des souris humanisées, telles que les thérapies par lymphocytes T à récepteur d'antigène chimérique (CAR) pour le cancer, les thérapies antivirales et les thérapies géniques pour de multiples maladies monogénétiques Les modèles de souris humanisées ont été et sont toujours d'une grande valeur pour le domaine de la thérapie génique car ils permettent une compréhension plus fiable des approches thérapeutiques parfois compliquées telles que les stratégies thérapeutiques d'édition de gènes récemment développées, qui cherchent à corriger un gène à son locus génomique endogène.De plus, les modèles murins humanisés, qui sont d'une grande importance avec en ce qui concerne le test de nouvelles technologies vectorielles in vivo pour évaluer l'innocuité et l'efficacité avant les essais cliniques, aider à accélérer la traduction critique des résultats de base aux applications cliniques."

Lire l'article complet, ci-dessous.

Humanized mice are precious tools for evaluation of hematopoietic gene therapies and preclinical modeling to move towards a clinical trial.

Brendel C, Rio P, Verhoeyen E.Biochem Pharmacol.

2020 Apr;174:113711.

doi: 10.1016/j.bcp.2019.113711. Epub 2019 Nov 11.

PMID: 31726047

https://pubmed.ncbi.nlm.nih.gov/31726047/

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