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In Loving Memory 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.

In this issue: New proof-of-concept article on RNA Therapeutics and Base/Prime Editing for SDS; And, a review of diagnostic testing for Exocrine Pancreatic Insufficiency (EPI) 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 Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

From the Founder, Dr. Eszter Hars Dear SDS community, I am delighted to announce that the SDS Alliance has initiated a project with The Jackson Laboratory (JAX) to develop a mouse model for SDS! This is very exciting because for decades, we have wanted a cure for SDS and a mouse model is the key first step that will allow new therapy development to begin. Many new therapeutic approaches — such as gene therapy, antisense oligonucleotides, and small molecule drugs — are waiting to be applied to SDS. With a good mouse model, all these possibilities will open up! Wouldn’t it be wonderful if we could just take a pill to restore our bone marrow function? A medicine like that would be one of the many things that researchers could work on as soon as the mouse model is ready! This project represents the first step of our strategy. We have recruited JAX — the leading mouse model developer — to create the mouse model for us. JAX has over 2300 employees, most of whom are PhD scientists, and $500 million of revenue a year. If you know any scientists working on therapy development — whether for cancer, diabetes, immunology, or blood disease — chances are they are using mouse models from JAX. I know that because I have used them in my own work! The project will include two parts: Create the mouse model (introduce SDS disease genes into mice using CRISPR and breed) for $150,000; Characterize the model (for example, how does SDS present in mice compared to human SDS? Do the mice get pancreatic problems or neutropenia?) for another $150,000. JAX has agreed to use their NIH grant funding to cover the model creation cost for us! Essentially, JAX is creating the mouse model for free; all we have to do is characterize it. I am very appreciative of JAX for helping our community. I am thrilled that the SDS Alliance is the first patient organization that JAX chose to support this way! They like the fact that we speak their scientific language — which they had never seen with other patient organizations — and they are convinced of our ability to take their mouse model to the next level — therapy development. Just like we envisioned in our strategy, we are leveraging the NIH grant through JAX! The mouse model is the first step toward finding a cure. Are you ready to turn hope into action? To complete the mouse model, the SDS Alliance is launching a “Turn Hope into Action” fundraiser to raise $150,000. We will commission the best experts to characterize the model and make sure they deliver. Once developed, we will make the mouse model available to any researcher, anywhere in the world, who studies SDS. This mouse model will also enable us to attract therapy development experts, including biotech companies, to test and refine their new therapies for SDS. I look forward to a future where we no longer have to worry about bone marrow failure or leukemia. The future is in our hands! Our strategy is working, but we can’t do it alone. We need your support! Together, let’s turn hope into action, and action into results! Please donate today and help us fundraise. I'd be happy to help set up your own fundraiser. (For international supporters, we have set up a Facebook fundraiser that doesn't charge credit card fees.) Sincerely, Eszter Hars, Ph.D. President and CEO SDS Alliance connect@SDSAlliance.org

In this issue: Unusual SDS case report from Uruguay about an adult patient; And, what exactly is a Rare Disease anyway (a project by RDI)? 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:

In this issue: Expert consensus on the management of hematological complications in SDS by The European Society for Blood and Marrow Transplantation-Severe Aplastic Anaemia Working Party. Also, advances in newborn screening programs and the inclusion of Shwachman-Diamond Syndrome (SDS) 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:

After the successful launch of the mouse model project last year and advancing it to phase two this year, we have expanded our efforts to develop additional critical research tools to enable the development of therapies and cures for SDS. These projects are part of our focus to develop research tools and infrastructure as outlined in our roadmap. 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

In Loving Memory 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.

"I needed to push for what I thought my daughter needed. I was her voice." Shares Nora's mom Lisa. Read this US family's story, here. If you would like to support Lisa's extraordinary fundraising efforts, you can find her current campaign page here. Nora Leigh Superina: 7 lbs 1 oz, 20 inches of perfection. On March 16th, 2020, our sweet, beautiful, Nora Leigh was born. My pregnancy was uneventful and Nora was full term and 7 lbs 1 oz. She spent a short time in the NICU for swallowing some amniotic fluid that would just not absorb because, as the delivery doctor put it, she “flipped out on a wave” of amniotic fluid after just one quick push. Nora was perfect. She was a beautiful and happy baby who took to breastfeeding wonderfully, like her three sisters before her. Having three daughters prior to Nora’s birth, I was no stranger to motherhood, which is why when Nora seemed a little different than my other girls, I began to worry. Most babies leave the hospital lower than their birth weight, but it is expected that within those first few weeks of life, they gain that weight back and then some. Nora did not. ...when Nora seemed a little different than my other [three] girls, I began to worry. The Infant Stage and my Denial Nora often seemed weak and floppy to me. It was not uncommon for her to look exhausted with dark bags under her eyes, even after a decent night of sleep. She never really “rolled” over, it was more like she “plopped” when she tried to turn her body. She was very gassy and often seemed uncomfortable. She had a great appetite and nursed on demand, yet she was gaining weight slowly. Despite her slow gain, Nora always followed her own curve, so I was often told, “She is just small, don’t worry” or “She’s petite, like her sisters.” When strangers saw her they assumed she was at least 3 months younger than she actually was. “She is petite.” “She is petite.” “She is petite.” This is what I told them. This is what I told myself. At first, I believed this. I desperately wanted to believe this. How could anything be wrong with my beautiful little girl? She was perfect. “She is petite.” “She is petite.” “She is petite.” This is what I told them. This is what I told myself. Something Just Isn't Right- Acceptance Nora was growing up and I did what I did with my other daughters, what our pediatrician recommended, I introduced baby food. Her stools became excessive and oh so stinky. It seemed like anytime she ate or drank anything, she would have a bowel movement. I began keeping a notebook where I logged everything she ate, drank, her naps, how often she went to the bathroom, what the stools looked like, how she slept... everything. This notebook became an obsession for me and it was at this point that I realized that I knew something was wrong. I had known for some time now... why else would I be so obsessive with keeping track of everything she consumed and everything she did? I did not do this with my other children. My mother’s intuition told me something was wrong and Nora needed my help. I began keeping a notebook where I logged everything she ate, drank, her naps, how often she went to the bathroom, what the stools looked like, how she slept... everything. This notebook became an obsession for me and it was at this point that I realized that I knew something was wrong. Failure to Thrive- The Official Start of Our Diagnosis Journey At Nora’s 6 month checkup with her pediatrician, Nora was labeled “Failure to Thrive.” Even though she was never on the charts for her weight and always at a very low percentile for her height, for the first time, she had fallen off her growth curve. Regardless of what her weight was at that appointment, I had gone into that office with the intention of asking for a script to get bloodwork. Nora’s pediatrician agreed that this was a good idea and off we went for what would be the first of many blood draws. Soon after, the results came back and showed that she had elevated liver enzymes. I remember a sudden rush of fear and having to sit down with Nora fidgeting on my lap. I was told that this could be due to an infection and not to be overly concerned, but they did want to make sure there was nothing to worry about. We were sent straight to Zwanger-Pesiri for a pelvic and abdominal ultrasound, which showed that everything looked normal. This was reassuring, but the fear was still there because we still didn't have an explanation for all of her symptoms. We were given a script for a sweat test at the hospital and were referred to a Gastroenterologist. The sweat test was negative and we were able to rule out Cystic Fibrosis. The gastroenterologist did a cholestasis panel, more bloodwork, and checked her fecal fat in a stool sample, but regretfully, did not check her fecal elastase. If she did, she would have seen that Nora had exocrine pancreatic insufficiency. Looking back, I wish I had pushed more for the doctors to investigate why her stools were so irregular rather than accepting the statement that “frequent bowel movements were normal for babies.” But now I’m taking you closer to the end of the diagnosis journey, I digress. Over the next few months Nora had more blood draws and doctor appointments than any baby should. No one had answers for us and we kept getting referrals to different specialty doctors: a hepatologist, endocrinologist, cardiologist, neurologist, pulmonologist, and a geneticist. Over the next few months Nora had more blood draws and doctor appointments than any baby should. No one had answers for us and we kept getting referrals to different specialty doctors: a hepatologist, endocrinologist, cardiologist, neurologist, pulmonologist, and a geneticist. I had her evaluated through Early Intervention for physical therapy, which she did not qualify for, but I knew she needed due to her hypotonia and delay in gross motor skills. This is when I first realized that I couldn't be that mom who sat back and listened to what everyone said. I needed to push for what I thought my daughter needed. I was her voice. So, I had her reevaluated and ended up going through insurance to get her PT when she did not qualify for the second time. Her visits to cardiology, endocrinology, and neurology suggested no problems with these areas and Nora’s essential team of doctors became her geneticist, hepatologist, and gastroenterologist. At this point everyone seemed to believe that Nora had an unknown metabolic or mitochondrial disease that was affecting her liver. She had a microarray, a whole exome sequencing, metabolic and mitochondrial panels, lysosomal storage disease panels, and other testing specific to certain metabolic diseases, but nothing explained her “Failure to Thrive,” elevated liver enzymes, and stools. Everything came back negative, VOUS [Variant of Unknown Significance], or an unrelated carrier status. I asked if there was any more testing that can be done and learned of the Whole Genome Sequencing (WGS). We were told that there was a ten percent yield and the fact that the WES came back negative suggested that it was unlikely that it would give us any answers. I needed to push for what I thought my daughter needed. I was her voice. On May 5th, 2021, Nora had a liver biopsy, which showed advanced liver disease due to advanced fibrosis and fat. The doctors did not recognize “the process” that was occurring in her liver and decided that it was of metabolic origin. In the coming months she would get sick frequently. She had multiple respiratory infections, eye infections, ear infections, a urinary tract infection, and multiple episodes of cellulitis from bug bites. I feared her getting sick, because I just knew her body was not reacting to common illnesses, like colds, the way that a healthy child’s body would. We had quite a few Emergency Room visits from high fevers and she ended up with Pneumonia from her “common colds” twice. I was frantic for answers. In the coming months she would get sick frequently. She had multiple respiratory infections, eye infections, ear infections, a urinary tract infection, and multiple episodes of cellulitis from bug bites. I trusted Nora’s doctors and I knew that they cared, but no one was more invested in her well being than me, so I dove into my own research. During the day I was a mom and high school teacher, at night I became a doctor, a researcher. I spent hours upon hours searching for a diagnosis for my baby. Like I said, I knew the doctors were doing their part and that they wanted answers, but nobody will ever want answers as much as a mother who has to watch her baby suffer. Every night I sat at my laptop with no less than 10 tabs up on my screen. I would go back and forth between Facebook groups entitled “Parents of Failure to Thrive Children,” “Parents of Children with an Undiagnosed Disease,” etc. I researched doctors who specialized in metabolic diseases and sent them emails, even found their personal contact information on social networking sites and contacted them directly. I had no shame. I became that “annoying'' parent who called over and over to check if lab results were in or if they had any suggestions on something I could be doing differently to help my daughter. “Keep doing what you're doing,” was always the response. So I kept doing what I was doing, praying that the doctors were doing the same. I applied to the Undiagnosed Disease Network and I emailed more doctors. I did safe trial diets and asked for more testing from the doctors. Through the online groups I contacted parents of children who had symptoms similar to Nora’s then dove into diagnosis after diagnosis trying to determine if any of them matched up with Nora’s symptoms. I spent hours upon hours searching for a diagnosis for my baby. [...] nobody will ever want answers as much as a mother who has to watch her baby suffer. Every night I sat at my laptop with no less than 10 tabs up on my screen. June 28th, 2021. “We have a diagnosis for your daughter.” We were on a family vacation in Florida and just finishing up breakfast when my cell phone rang. It was Nora’s geneticist. The first thing she asked was when we were planning on coming home. The fear was immediate. Why would this question be asked unless there was an urgency in getting Nora home? Her second question was if my husband, Graig, was around. Graig and I proceeded to the back bedroom of the condo where we were told, “We have a diagnosis for your daughter.” We didn’t know it then, but that one sentence would change our lives forever. With that sentence, Shwachman-Diamond Syndrome, a disease that we had never heard of before, had instantaneously become a significant part of our life. The rest of the conversation was a blur, but we were basically told of the new team of doctors this disease would require her see: a hematologist, gastroenterologist, pulmonologist, hepatologist, and other doctors as needed. Her main doctor was going to be a hematologist because Nora was just diagnosed with an ultra rare blood and bone marrow disease. We were then told that there is no treatment or cure, yet, just aggressive management. The phone call ended with her saying that there was not much more information for her to give us because she was not very familiar with SDS and she recommended that we not google too much and try to enjoy the rest of our vacation. We hung up the phone and proceeded with our morning on autopilot in a fog of fear. I slathered the girls in sunblock and helped them into their bathing suits, all the while fighting back the urge to scream or cry. I needed to know more, but feared what I would find out. My phone itched in my pocket. “We have a diagnosis for your daughter.” We didn’t know it then, but that one sentence would change our lives forever. With that sentence, Shwachman-Diamond Syndrome, a disease that we had never heard of before, had instantaneously become a significant part of our life. At the pool, I waited until the girls were settled, swimming in the water with their daddy. I sat in a lounge chair under an umbrella and pulled out my phone, “What is Shwachman-Diamond Syndrome?” I scrolled and clicked. The first link I clicked had the word “adulthood” in the first sentence. Adulthood. My baby girl would become a little girl, then a big girl, and one day, an adult. Relief flooded through me. We had time. Time to find treatments and a cure. Over the next few hours I made calls to Nora’s team of doctors. They sent me scripts for stool samples to check for exocrine pancreatic insufficiency, so that Nora can start on Creon, an enzyme replacement medicine that would allow her to digest food properly. I set up appointments with all of the doctors that she would need to see when we got back to New York. The first link I clicked had the word “adulthood” in the first sentence. Adulthood. My baby girl would become a little girl, then a big girl, and one day, an adult. Relief flooded through me. We had time. Time to find treatments and a cure. From all these phone calls with Nora’s doctors, one statement stands out in my mind, “When it comes to rare diseases, parents find the cures.” This doctor also suggested I find an online support group and align myself with like-minded parents who understand the importance of research. Parents who know that action is needed, that sitting back and waiting for things to happen is not an option. Parents Will Find the Cure My fundraising began that afternoon at the Florida pool, and since then, as a family, we have raised over $80,000. [Visit our visit her fundraising page here]. I will stop at nothing to find treatments and a cure for my sweet daughter and others like her. I will share her story with anyone who will listen. I will spread awareness, I will raise funds, I will find a cure...because that's what moms of children with rare diseases do. I will stop at nothing to find treatments and a cure for my sweet daughter and others like her. I will share her story with anyone who will listen. I will spread awareness, I will raise funds, I will find a cure...because that's what moms of children with rare diseases do. Having a diagnosis for Nora has been a blessing because we now know what we are up against. Like the saying goes, knowledge is power. Now, Nora has an amazing team of doctors who go above and beyond and listen to my concerns. If they don’t have all the answers (because who really does when it comes to rare disease?) then they find someone who does. Nora has a fever protocol and she takes medications and vitamins that her body needs to thrive. We know what to look for and we know how to deal with health problems as they come. We are connected with an amazing group of people who “get it” and are there to listen or help with any day to day questions. We will be okay. Nora will be great. If anyone reading this can take anything out of Nora’s story, it would be that a mother’s instinct is always right. Trust yourself, you know your child. Do the research and don’t be afraid to make demands from doctors and ask for the extra tests and bloodwork. If you finally get a diagnosis and it turns out to be a rare disease, like SDS, do more research! Spread awareness, fundraise, and align yourself with like-minded people who have similar goals. You are your child’s biggest advocate and you will make a difference in your child's life! Last, but not least, SHARE your story because you never know who is staying up late researching their child’s symptoms in hopes of possibly stumbling across something that can help them get answers. You can make a difference. Spread awareness, fundraise, and align yourself with like-minded people who have similar goals. You are your child’s biggest advocate and you will make a difference in your child's life! Addendum- October 12, 2021 Sometimes life throws you a curveball. Sometimes life throws you two. Yesterday, October 12, 2021, I received a phone call that the genetic testing for my other daughters: Maria, Emma, and Kayla, had resulted. (It was recommended that we have them tested, regardless of them not having any obvious symptoms, because they each have a 50% chance of being a carrier, a 25% chance that they are fine and a 25% chance of being positive). Maria and Emma are carriers of the genetic mutation that causes SDS. But, Kayla....Kayla, my sweet 3-year-old, chubby faced , happy girl, was positive. What did I miss? My mind raced and is still racing with scenarios...the time she had an ear infection that took two rounds of antibiotics to go away...when she was a newborn and her body was covered in a rash that turned out to be a yeast infection...she’s on the shorter side, but my husband and I would never be considered tall. Weight wise, she is the biggest of all my girls and she has hit all of her milestones. When Kayla gets sick, she recovers. When Kayla gets bug bites, she does not get cellulitis. What did I miss? Nothing. Kayla is not like Nora...and if you really think about it, Nora being born may have saved Kayla’s life. Again, there is power in knowledge, and now we know. Now we can monitor and keep her as healthy as possible. Kayla may not exhibit the typical SDS symptoms right now, but maybe one day she will, and knowing gives us the opportunity to get ahead of it. I thank God every day for giving me these little girls and I trust in His plan. I know with all my heart that I was meant to be their mommy and now we have two perfect girls to fight for… to find a cure for. Nora and Kayla’s Quest for a Cure. We got this. Sometimes life throws you a curveball. Sometimes life throws you two. [...] I know with all my heart that I was meant to be their mommy and now we have two perfect girls to fight for… to find a cure for. Nora and Kayla’s Quest for a Cure. We got this. [Editorial note: Thank you Lisa for your incredible fundraising efforts, success, resilience, and positivity. Your work has a profound impact and all the donations from your efforts go 100% to research. To donate to Lisa's fundraiser, visit her fundraising page here.]

The SDS Alliance focuses on making therapies and cures a reality for SDS patients worldwide. A major stakeholder in this journey is the FDA (the US Food and Drug Administration). Engaging with the FDA early and meaningfully is a high priority on our roadmap. 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.

This October, we conducted the third annual global virtual fundraiser to support SDS research. The theme this year was THREE MILLION STEPS CLOSER TO #CURESDS. 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!

September 30th is Rare Cancer Day. We marked the day by taking action and meeting with the White House Cancer Moonshot initiative in collaboration with our colleagues at the Heritable Cancer Prevention Coalition (HCPC). Our goal is to assist the Cancer Moonshot Initiative with its ambitious goal of cutting the age-adjusted cancer death rate by at least 50% over the next 25 years – with our focus being on heritable blood cancers. 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!

We are so honored and excited to announce that we won the JumpStart Research Tools Matching Grant through The Orphan Disease Center (ODC) at the University of Pennsylvania! In partnership with the Coriell Institute, this grant will support the creation of high-quality, Shwachman-Diamond Syndrome patient-derived induced pluripotent stem cell lines (iPSCs). The breakthrough technology of iPSCs has quickly become an important tool for modeling and investigating human disease, screening drugs, and providing an unlimited supply of human tissue for research, and we jumped at the opportunity to bring this tool to the SDS research community. 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.