<![CDATA[Shwachman-Diamond]]>https://www.sdsalliance.org/blogRSS for NodeTue, 29 Nov 2022 11:45:21 GMT<![CDATA[2022 Annual Global Virtual Fundraiser - Three Million Steps Closer to #CureSDS - Huge Success Again]]>https://www.sdsalliance.org/post/steps2022634add7f7cb743c25f035025Sat, 22 Oct 2022 23:26:56 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceThis 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!

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<![CDATA[SDS Alliance meets with the White House Cancer Moonshot Team]]>https://www.sdsalliance.org/post/sds-alliance-meets-with-cancer-moonshot-team-september2022633bce84362ad74e40cb0b26Tue, 04 Oct 2022 06:28:13 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceSeptember 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!

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<![CDATA[SDS Alliance is Awarded JumpStart Grant for iPSC Development]]>https://www.sdsalliance.org/post/jumpstart-grant-ipsc6319f8e0fda5ba9b3efc813bThu, 08 Sep 2022 15:06:26 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceWe 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.
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<![CDATA[Mouse Model Project Update: Phase I complete!]]>https://www.sdsalliance.org/post/mouse-model-phase-i-complete630d3d7888affa77f95b741fMon, 29 Aug 2022 22:56:47 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceDear SDS community,

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.

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<![CDATA[SDS & Science Snapshots (2022-08-21)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-08-216301ab0ec8a1693127a8d1f0Sun, 21 Aug 2022 04:00:00 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: What is Congenital Exocrine Pancreatic Insufficiency; Can genetic disorders be treated in the womb? A case report in Cystic Fibrosis suggests so.

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.

https://youtu.be/dvWDRRyT9As

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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<![CDATA[SDS & Science Snapshots (2022-07-31)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-07-3162e6870ca8e0f54e1ddf6d84Sun, 31 Jul 2022 17:59:51 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: What is a protein 3D structure and why it matters; New article on the structure and dynamics of the SBDS protein; DeepMind is now publishing the predicted structures of over 200 million proteins

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:

https://youtu.be/hok2hyED9go

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:

https://youtu.be/1SQZsdDrjXE
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.

https://youtu.be/f19o38drW8s

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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<![CDATA[SDS & Science Snapshots (2022-07-23)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-07-2362dc14ab1cdd24d6e1401160Sun, 24 Jul 2022 11:35:01 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: What is neutropenia and how does it happen in SDS; Study highlights the multibillion dollar burden of rare disease

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.

https://youtu.be/qYDM0YU0KQE

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:

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

https://youtu.be/FZxf1QDcEO0 https://youtu.be/WUBDyowXAcE

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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<![CDATA[SDS et les aperçus de la science (10 juillet, 2022)]]>https://fr.sdsalliance.org/post/sds-science-snapshots-2022-07-10-fr62d42baee64f0f75609a5efeSun, 17 Jul 2022 15:46:03 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceDans ce numéro : CRISPR-Cas9 fête ses 10 ans; La promesse de la thérapie génique pour les maladies rares et le syndrome de Shwachman-Diamond (SDS)

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".

https://youtu.be/6tw_JVz_IEc

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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<![CDATA[SDS & Science Snapshots (2022-07-10)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-07-1062cae0e77e2fb509a11a50deSun, 10 Jul 2022 17:25:10 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: CRISPR-Cas9 turns 10; The promise of Gene Therapy for Rare Disease and Shwachman-Diamond Syndrome (SDS)

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!

CRISPR-Cas9 turns 10 years old

CRISPR debuted 10 years ago, in a paper hardly anyone noticed: in June 2012, a joint press release went out from the U.S. Department of Energy and the Lawrence Berkeley National Laboratory announcing a new paper in Science “Programmable DNA Scissors Found for Bacterial Immune System”.

In it, the authors pointed out that the discovery could lead to a new “editing tool for genomes.” The paper has now been cited by more than 15,000 publications and downloaded nearly 65,000 times. In it, the now famous Nobel Prize winning authors - Jennifer Doudna and Emmanuelle Charpentier - explained the inner workings of a system called CRISPR/Cas9.

Although the incredible impact wasn't immediately recognized by the public, now a decade later there is hardly anyone who hasn't hear the term. CRISPR has been used to manipulate the genomes of organisms across every branch of the tree of life, including humans. It’s now being tested to treat dozens of inherited diseases - including many rare diseases - , with companies planning to ask regulators for approval of the first CRISPR-based medicine as soon as later this year.

Read an article by STAT about their interview with Dr. Doudna at the University of California, Berkeley, where she directs the Innovative Genomics Institute.

So, what exactly is the CRISPR-CAS9 technology?
In short, according to the NIH-NCI, it is laboratory tool used to change or “edit” pieces of a cell’s DNA. CRISPR-Cas9 uses a specially designed RNA molecule to guide an enzyme called Cas9 to a specific sequence of DNA. Cas9 then cuts the strands of DNA at that point and removes a small piece, causing a gap in the DNA where a new piece of DNA can be added. CRISPR-Cas9 is a breakthrough in science that will have important uses in many kinds of research. In cancer research, it may help to understand how cancer forms and responds to treatment as well as new ways to diagnose, treat, and prevent it.

Watch this great overview by TED-Ed. We have added some more on our "Understanding SDS Science" page, too.

https://youtu.be/6tw_JVz_IEc

Want to learn more? Check out this amazing resource by the Innovative Genomics Institute, here.

The promise of Gene Therapy for Rare Disease and Shwachman-Diamond Syndrome (SDS)

The majority of the 10,000+ rare diseases are genetic in nature - meaning there is a "typo" or change in the sequence of a gene that is necessary for the healthy function of the human body. If we could fix the specific defect in the genome, in the right organs or tissues, we would be able to deliver cures for the millions of people suffering from rare diseases. Shwachman-Diamond Syndrome (SDS) falls into this category, too. There are a lot of factors that make SDS a fantastic target for gene editing. It is a singe gene disorder - caused by a mutation is just one gene - and the particular mutation (or "typo") is very uniform. Specifically, Over 90% or people with SDS have mutations in a gene called SBDS, and almost all of these patients have at least one "splice site mutation" (258+2T>C). Another aspect that makes SDS a great model disease is the target organ that would need to be reached: the bone marrow. The bone marrow is much easier to reach than the brain, for example. Ex vivo gene editing technology is feasible: Hematopoietic stem cells can be obtained from patients in the same way as people donate stem cells for transplant. Once harvested, the cells can be "edited" - the mutation fixed. Then, the "fixed" cells can be infused back into patients, just like during a traditional stem cell transplant.

Of course this is all easier said than done, and a lot of research efforts is ahead of us. The good news is that a whole research laboratory under the direction of Dr. Brendel at Boston Children's Hospital is dedicated to this work. They are focused on developing approaches to customize the CRISPR-Cas9 machine to efficiently edit the most common SDS causing mutations in SBDS. This work is still in the early stages and likely years away from getting into patients, but certainly an approach that we must explore. We will provide more details and insights, soon. We are dedicated to support this work in any way we can. In particular, our mouse model project seeks to provide a critical tool to accelerate this work, as it harbors the exact human sequence that needs to be targeted by CRISPR-Cas9.

Dr. Brendel published a review article recently highlighting how and why "Humanized mice are precious tools for evaluation of hematopoietic gene therapies and preclinical modeling to move towards a clinical trial".

"The most significant contributions made by these humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, screening of anti-cancer therapies and their use as preclinical models for gene therapy applications. This review article focuses on several gene therapy applications that have benefited from evaluation in humanized mice such as chimeric antigen receptor (CAR) T cell therapies for cancer, anti-viral therapies and gene therapies for multiple monogenetic diseases. Humanized mouse models have been and still are of great value for the gene therapy field since they provide a more reliable understanding of sometimes complicated therapeutic approaches such as recently developed therapeutic gene editing strategies, which seek to correct a gene at its endogenous genomic locus. Additionally, humanized mouse models, which are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to clinical trials, help to expedite the critical translation from basic findings to clinical applications. "

Read the full article, below.

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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<![CDATA[SDS & Science Snapshots (2022-07-03)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-07-0362b8eade997098b5acb33bc7Sun, 03 Jul 2022 10:30:07 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: IRDiRC Working Group Recommendations for rare disease patients; The Access to Rare Indications Act could be a game changer for millions of Americans; New Case Report from Romania on Novel Biallelic Variants in DNAJC21.

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!

Recommendations from the IRDiRC Working Group on methodologies to assess the impact of diagnoses and therapies on rare disease patients

The IRDiRC Working group recently published an article making recommendations for improving treatments for rare disease patients. In 2017 the International Rare Diseases Research Consortium (IRDiRC) set its 10-year goal to “Enable all people living with a rare disease to receive an accurate diagnosis, care, and available therapy within one year of coming to medical attention.” The authors acknowledge that in order for this goal to be met, there must be transparency about the impact of every step of the diagnostic and therapeutic journey on patients’ lives. Their recommendations range from information that should be assessed by clinicians, healthcare providers, and insurance companies to more comprehensively care for rare disease communities.

“The goal many of us working in research have, is to help these rare disease patients and families solve some of the greatest challenges in receiving a proper diagnosis and treatment plan for a rare disease,” said David A. Pearce in IRDiRC's recent press release. “The work done by this workgroup recommends new metrics for the development of new tools to ensure more accurate diagnosis and to assess the impact of therapies and diagnosis on rare disease patients.”

In the ,article the abstract summarized their finding: "Rare disease patients face many challenges including diagnostic delay, misdiagnosis and lack of therapies. However, early access to diagnosis and therapies can modify the management and the progression of diseases, which in return positively impacts patients, families and health care systems. The International Rare Diseases Research Consortium set up the multi-stakeholder Working Group on developing methodologies to assess the impact of diagnoses and therapies on rare disease patients. Using the patients’ journey on the diagnostic paradigm, the Working Group characterized a set of metrics, tools and needs required for appropriate data collection and establishment of a framework of methodologies to analyze the socio-economic burden of rare diseases on patients, families and health care systems. These recommendations are intended to facilitate the development of methodologies and to better assess the societal impact of rare diseases."

The Access to Rare Indications Act could be a game changer for millions of Americans

The Access to Rare Indications Act, introduced to Congress in late 2021, aims at addressing a common challenge for rare disease patients: the off-label use of medication.

Because rare diseases often lack approved therapeutics, clinicians often rely on the use of drugs approved for other disorders to manage symptoms. So what is the problem? You guessed it: the cost that falls on patients and families. Off-label use of medication can become prohibitive because it is not always covered by insurance companies. Overcoming this barrier by covering off-label drug use for rare disease patients is a crucial step in making therapies more accessible.

In a New Case Report from Romania, Clinicians report Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype, and provide a comprehensive review of other cases reported in the literature.

The authors refer to the disorder as "bone marrow failure syndrome type 3", but some consider it an "SDS-like" syndrome, as we discussed recently in an other Snapshot post: https://www.sdsalliance.org/post/sds-science-snapshots-2022-03-20.

In addition to a very detailed case report, the authors summarize and compare the findings of 17 other patients with biallelic variants in DNAJC21, and highlight in their discussion the challenges and importance of timely genetic diagnosis.

"Bone marrow failure syndromes represent a diverse group of hematological disorders implicating single-line cytopenia or pancytopenia that may lead to the indication for hematopoietic stem cell transplantation (Bluteau et al., 2018). They may be acquired or inherited. Recognizing the inherited nature of bone marrow failure is crucial to prevent inappropriate treatment with immunosuppressant agents and to offer hematopoietic stem cell transplant with an adapted regimen, when needed. Importantly, identifying the genetic cause will help select the healthy donor and provide genetic counseling to the family (Barhoom et al., 2021). Even more, understanding the genetic cause may improve the management of several associated syndromic features. This patient had a late molecular diagnosis that led to some unnecessary treatments, such as cow milk protein restriction for 1 y and 6 months. In addition, the family had another child where informed genetic counseling was not possible in the absence of a molecular diagnosis. Fortunately, none of the siblings carry the variants.

The DNAJC21 gene was first associated with bone marrow syndrome type 3 in the year 2016 (Tummala et al., 2016). This is one of the reasons why despite several genetic tests performed, a diagnosis was not established for this child. Panels performed did not include the DNAJC21 gene, while the exome analysis did not identify the two variants in DNAJC21 to be associated with bone marrow failure. Genome sequencing performed in 2020 aimed to evaluate variants that could have been missed by the exome sequencing; however, it revealed the two exonic variants in the DNAJC21 gene, at the time recognized to cause disease, thus showing the importance of automated reinterpretation of negative exomes. Even more, there are probably other unknown genes that cause bone marrow failure, as suggested by other authors (Tummala et al., 2016; Dhanraj et al., 2017)."

Read the full article, below.

Case Report: Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype: An Odyssey to Diagnosis.

Chirita-Emandi A, Petrescu CA, Zimbru CG, Stoica F, Marian C, Ciubotaru A, Bataneant M, Puiu M.Front Genet. 2022 Apr 8;13:870233.

doi: 10.3389/fgene.2022.870233. eCollection 2022.

PMID: 35464845

https://pubmed.ncbi.nlm.nih.gov/35464845/

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<![CDATA[SDS & Science Snapshots (2022-06-25)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-06-2562b777a183bb34175852995fSat, 25 Jun 2022 21:56:06 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: Rare-X report provides update on the true number of rare diseases; new review article on bone marrow failure disorders by Dr. Dokal (UK).

Welcome to our regular updates on all things SDS and Science - now back after a short summer break. 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!

Rare-X Report on the Power of Being Counted: 10K+ Rare Diseases

Science and public health are constantly evolving through new insights and learning. When discussing rare diseases, it is common to mention that there are around 7,000. A recent report from Rare-X, a nonprofit focused on rare disease patient data collection and advocacy, has performed an updated count using existing databases and estimated that there are currently around 10,800 rare diseases, of which only 500 — or less than 5% — have available treatments.

It is well known that rare disease patients face many inequity challenges — diagnostic, therapeutic, management, and financial, just to name a few. These challenges require paradigm shifts in our health cares systems; accurate counts of our communities are a crucial step in advocating for our collective needs and making sure nobody is left behind.

New Review Article by Dr. Dokal on Inherited bone marrow failure in the pediatric patient

Dr. Dokal from the UK published a new review article on bone marrow failure syndrome. A review article is a scientific peer reviewed article that summarizes multiple other published work to provide new insights and perspectives. As the title suggests, this article provides an overview on bone marrow failure syndromes. Bone marrow failure syndromes are a group of genetic disorders that cause a challenge for the cells in the bone marrow to divide and produce blood cells. Shwachman-Diamond Syndrome is one such disease and is considered a bone marrow failure disorder for this reason, but it also falls into several other categories of diseases (such as Congenital Neutropenia, Primary Immune Deficiency, etc...).

SDS is also a blood cancer (hematological malignancy) pre-disposition disorder, and as such our focus here at the SDS Alliance is to accelerate and drive therapy development that can decrease the stress on the bone marrow cells and thereby reduce the chance of blood cancer ever occurring. We are also investing in advocacy in this area. More information coming soon.

Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with one or more additional abnormalities in addition to the blood forming system, such as Pancreatic Exocrine Insufficiency (PEI) in case of Shwachman-Diamond Syndrome (SDS). BM failure, which can involve one or more cell lineages (red blood cells, white blood cells, and platelets), often presents first in childhood. Some patients may initially be labeled as having idiopathic aplastic anemia or myelodysplasia or neutropenia, without identifying the underlying cause. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how this is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways: DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes.

Many of these disorders are associated with an increased cancer risk and therefore research into these diseases have provided insights into human development and cancer.

In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder.

Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly for patients with FA and DC. Management of some other complications, such as cancer, remains a big challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and small molecule drugs that target disease-specific defects.

Read the full review article, below.

Inherited bone marrow failure in the pediatric patient.

Dokal I, Tummala H, Vulliamy TJ.

Blood. 2022 May 23:blood.2020006481. doi: 10.1182/blood.2020006481.

Online ahead of print. PMID: 35605178

https://pubmed.ncbi.nlm.nih.gov/35605178/

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<![CDATA[SDS & Science Snapshots (2022-05-08)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-05-086278648d79bfa0cc43ae68dbMon, 09 May 2022 01:03:56 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: Dr. Bezzerri provides an update on a therapeutic approach targeting premature termination codon (PTC) mutations in SDS, or the c.183-184TA>CT mutation in the SBDS gene to be more specific.

Welcome to our weekly updates on all things SDS and Science. 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!

Progress on the development of novel therapies targeting the c.183-184TA>CT mutation in the SBDS gene.

Thank you Dr. Valentino Bezzerri for the detailed overview and summary, to put your latest publication into context.

What is the significance of the c.183-184TA>CT mutation in SBDS gene?

A large percentage of SDS patients carry the nonsense mutation c.183-184TA>CT in addition to the most common … “splice site” mutation. For instance, the c.183-184TA>CT mutation is present in more than half ( 56%) of SDS patients in the Italian SDS registry. This genetic variant leads to the generation of a premature termination codon (PTC) on the SBDS mRNA, which leads to a stop of protein translation at the 62nd amino acid position (K62X). mRNA that harbor such nonsense mutations are generally unstable and are rapidly degraded by a cellular mechanism known as nonsense mediated decay (NMD). If any mRNA could withstand the NMD, the resulting protein would be truncated and lose most (if not all) its function.

Is there any way to address this problem?

Stop codons can occasionally be overridden by near-cognate aminoacyl-tRNA, whose anticodon is complementary just for two of the three nucleotides. This process has been defined as translational read-through and may lead to abnormal termination of translation in 0.001-0.1% of total neo-synthesized proteins. Interestingly, this process is able to endogenously promote the read-through of PTC in 0.01-1% of cases. Even though this process is quite ineffective, it served to prove that mutations generating PTC may be corrected.

Could this mechanism be exploited pharmacologically with potential clinical benefit?

Aminoglycosides are a class of natural or semisynthetic antibiotics derived from actinomycetes. In eukaryotic cells, aminoglycosides may promote the binding of a near-cognate tRNA to a PTC, displacing eRF1, thus resulting in nonsense mutation suppression. The aminoglycoside geneticin (G418) was initially investigated in cystic fibrosis (CF) cell models harboring nonsense mutated CFTR gene. Further studies demonstrated the efficacy of aminoglycosides G418 and gentamicin in restoring a significant amount of functional CFTR and dystrophin proteins in CF and Duchenne muscular dystrophy (DMD), respectively. This reports therefore represented the proof of concept that the development of translational read-through inducing drugs (TRIDs) is feasible. Unfortunately, severe adverse effects caused by prolonged treatments with aminoglycosides, including auditory and vestibular toxicities have been reported, limiting the widespread clinical use of aminoglycosides for nonsense suppression therapy.

Are there any success stories for these types of drugs?

Ataluren (PTC124) was launched in 2007 by PTC Therapeutics (NJ, USA), as a potent TRID, without antibiotic properties. Compared with classical aminoglycosides, ataluren may promote a more selective readthrough of PTC, without affecting endogenous stop codons. Furthermore, ataluren has shown less toxicity and better safety than aminoglycosides. The use of ataluren as a potential therapeutic agent for genetic disorders has been early proposed for the treatment of DMD and CF. Most importantly, ataluren has been approved for the treatment of DMD in Europe. Data from clinical trials showed that chronic ataluren treatment is beneficial to DMD patients undergoing standard care, because it delays the progression of ambulation impairment and the worsening of pulmonary and cardiac functions. Interestingly, clinical studies revealed that the best results are observed in younger individuals, suggesting major benefits of early ataluren administration.

https://www.youtube.com/watch?v=gUFVvRN-CTU&t=438s

Why is ataluren not widely used?

Despite promising pre-clinical results, ataluren unfortunately failed in clinical studies of CF. The clinical development of ataluren for CF was therefore discontinued. These premises highlight that ataluren clinical benefit in people with CF may be highly variable. Consistent with this, also approximately 39% of patients with DMD did not exhibit protein resynthesis after treatment in a Phase 2a clinical trial.

The major pitfall of ataluren readthrough efficacy remains therefore its variable efficacy, which may depend on the sequence of the PTC (UAA

Has anyone tried this strategy on SDS?

To address Ataluren’s variable efficacy, an Italian research team headed by Dr. Valentino Bezzerri and Dr. Marco Cipolli (Cystic Fibrosis Center, University Hospital of Verona, Italy) tested a panel of ataluren analogues with improved in vitro efficacy. The authors tested the efficacy of analogues NV848, NV914, NV930, NV2445, and 5i on the restoration of SBDS protein expression in SDS cell models, in order to improve the clinical performance of this class of drugs. Second-generation analogues NV848, NV914, and NV930 were optimized from the lead compound NV2445, which showed promising results in correcting nonsense mutated CFTR expression in vitro, whereas the 5i compound was directly derived from ataluren. Molecule NV848 can restore SBDS protein synthesis in vitro to the same extent as ataluren, improving in vitro myelopoiesis, promoting neutrophil maturation and reducing the expression of dysplastic markers in these cells.

In addition, NV848 may have some advantages over ataluren, since it is quite hydrophilic, thus facilitating the selection of administration routes, and did not show any appreciable toxicity up to 1mM concentration in zebrafish experiments. Most importantly, NV848 has shown to be the best candidate for further development in SDS therapy, due to superior absorption, distribution, metabolism, and excretion (ADME) properties, compared to ataluren and other analogues.

There are three scientific publications on PubMed on this topic. You can find the latest article by Dr. Bezzerri, below, published last month.

Novel Translational Read-through-Inducing Drugs as a Therapeutic Option for Shwachman-Diamond Syndrome.

Bezzerri V, Lentini L, Api M, Busilacchi EM, Cavalieri V, Pomilio A, Diomede F, Pegoraro A, Cesaro S, Poloni A, Pace A, Trubiani O, Lippi G, Pibiri I, Cipolli M.Biomedicines.

2022 Apr 12;10(4):886.

doi: 10.3390/biomedicines10040886.

PMID: 35453634

https://pubmed.ncbi.nlm.nih.gov/35453634/

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<![CDATA[Ángel Leonardo's SDS Story from Mexico [Spanish and English]]]>https://www.sdsalliance.org/post/sds-story-angel-leonardo-mexico626b18e5095d0a8d3f216417Thu, 28 Apr 2022 23:15:27 GMTEszter Hars, Ph.D., President and CEO, SDS Alliance"My parents taught me that apart from receiving help, I must also help. I have a big heart and I am a teacher of life for my family, a warrior and the best gift of life for my parents." Angel Leonardo's mom Angli shares on his behalf. Read this beautiful family's story from Mexico, here.

[Original language: Spanish]

Hola, me llamo Ángel Leonardo, soy un bebé muy deseado y mexicano, nací en Cancún. En el país Mexico, hay un gigantesco desconocimiento de Shwachman Diamond. Casi no hay datos de dos niños más con Sds de hace diez años, yo era el único registrado en Mexico y ahora pude encontrar y orientar a una segunda niña en el norte de mi país, pero obvio debe haber muchos más si en Mexico somos casi 130 millones de personas. Este gran desconocimiento y falta de diagnóstico es lo que me ah hecho sufrir muchos estudios de más, dolorosos y repetitivos para encontrar que tenia. Nací de peso bajo y talla pequeña, tuve citomegalovirus intrauterino, y nací con anemia severa, y neutropenia grave, por lo cual pensaron tuve infección intrauterina y me llenaron de antibióticos pero no funciono.

No podía succionar leche, tenía muchos cólicos, me quede internado medio mes en hospital pero todo lo que comía me hacía daño y tenía popos muy aguadas y cólicos por horas y horas. Como no supieron que tenía, me mandaron a casa con extremos cuidados porque decían que si me quedaba más tiempo en el hospital corría riesgos de infectarme de algo más. Me confundieron mi insuficiencia pancreatica grave con alergia a la proteína de la leche de vaca, así que mi mamá hizo dieta especial y libre de lácteos para seguirme amamantando pero la grasa de la leche me seguía causando mucho dolor, los doctores decían que eso eran normal, había niños así, pero lloraba más de seis horas al día, me despertaba toda la noche, y sufría mucho.

Los primeros seis meses de vida tuve anemias severas por lo que me hicieron 4 transfuciones sanguíneas, después de los seis meses no volví a tener anemia, pero si seguían las neutropenias, por lo cual se me mando desde los 3 meses de edad filgastrim o neupogen inyectada por mi mamá semanalmente. Viajaba cada mes a otro estado y a la capital del país para ver médicos, sabían que tenía una falla medular pero en Mexico no existe el estudio genético para saber que tipo de falla medular tenía, así que por rifas y colectas logramos pagar el estudio genético, y se envío la muestra genética a Estados Unidos, de ahí pudimos saber que era síndrome de Shwachman Diamond, sin mutación, la versión más común, gracias a Dios.

Pero hasta los 8 meses o más entendieron que no tenía alergia a la proteína de la leche de vaca si no problemas en hígado y páncreas, y mucha falta de apetito por el mismo síndrome, así que por fin yo empecé a usar enzimas, creon, pero se niveló y encontramos las cantidades necesarias hasta que tenía como año y medio de edad.

Querían en el hospital de especialidades mejor capacitado del país, en la capital, obligatoriamente hacerme transplante de médula, pero mi mamá sentía en su corazón que era algo muy agresivo como para usarlo para prevenir la leucemia, y el citomegalovirus podía afectarme en las quimioterapias, solo teníamos a mi papá de fonador y eso significa solo 50% de probabilidad de éxito, y no dejaban que buscáramos otro donador, o usar ombligo, ellos decían que nuestra mejor opción era mi papá, por eso volvimos a conseguir dinero, tener deudas y mucho esfuerzo e hicimos una Inter consulta por internet con el hospital de Boston, donde hay especialistas en Shwachman Diamond, y nos explicaron que el transplante solo se autoriza si cumple con los requisitos que son: anemias y transfusiones de sangre continuas, muchas enfermedades graves o que se encuentren células cancerígenas en la biopsias de médula ósea, de lo cual yo solo tenia neutropenias, y problemas en deformidad de el tórax, hígado e insuficiencia pancreatica, y esas tres ultimas no cambiarían aún después del transplante de médula.

Boston nos explicó que el neupogen o filgastrim solo son de rescate cuando el niño se enferma, no un tratamiento a largo plazo a excepción de que me enfermara demasiado o mis neutropenias fueran muy graves, ya que todo medicamento tiene efecto secundario, y esta vacuna tiene un acelerador celular,así que si está en mi futuro la leucemia también la va a acelerar a desarrollarla antes.

Así que suspendimos el transplante pues por fin entendimos un poco mejor el síndrome, mis papás me siguen cuidando muchísimo, y tratando de que los días buenos sean los mejores del mundo, hacerme muy feliz y disfrutar día a día. Soy un niño muy sensible y noble, pero también amo reír, correr y ver libros, entendimos que tener una enfermedad rara no define quién soy, soy más que una enfermedad, soy un ser humano inteligente, cariñoso, único, y que no me debe limitar una enfermedad para ser feliz, tengo un nombre, no soy solo el familiar o El Niño enfermo, soy muy consentido por mis papás y familia y ya en seis meses tendré 4 años, empiezo a tenerle menos pánico a los doctores, a la gente y a la vida afuera, pero por el covid seguimos con filgastrim, y dios quiera pronto podamos suspender la inyección para ver mis reales neutropenias y vida sin esta inyección.

Tengo mi página en Facebook, Ángel Leonardo enfermedad Shwachman Diamond, tik tok ángel_leo_shwachmandiamond, y tenemos una página o grupo de apoyo para mexicanos y latinos en Facebook, síndrome de Shwachman-Diamond-apoyofamiliar-americalatina, para apoyar a familias que empiezan, dudas, o actualización de información (https://www.facebook.com/groups/844701606198176). Mis papás me enseñaron que aparte de recibir ayuda debo ayudar, tengo un gran corazón y soy un maestro de vida para mi familia, un guerrero y el mejor regalo de la vida para mis papás.

[English translation]

Hello, my name is Ángel Leonardo. My parents had a strong longing to have me, and finally I was born in Cancún, Mexico. In Mexico, there is very little known about Shwachman Diamond Syndrome. There is almost no record of any patients, except for two children with SDS within the past ten years. I was the only one registered in Mexico and only recently have I been able to connect with a second child (a girl) in the north of my country, but obviously there must be many more since Mexico has close to a 130 million people. This lack of knowledge and information has led to delays in my diagnosis and to more suffering through many more, painful and repetitive tests to find out what I had. I was born with low weight and small size, I had intrauterine cytomegalovirus, and I was born with severe anemia and severe neutropenia. They thought I had an infection in utero and filled me up with antibiotics after I was born, but it didn't work.

I couldn't drink milk, I had a lot of cramps, I was in the hospital for half a month but everything I ate hurt and I had very watery stools and cramps for hours and hours. Since they didn't know what I had, they sent me home with great concern because they said that if I stayed longer in the hospital I risked catching something else. They mistook my severe pancreatic insufficiency for an allergy to cow's milk protein, so my mom went on a special dairy-free diet to continue breastfeeding, but the milk fat was still causing me a lot of pain.

The doctors said that was normal, there were more children like that, but I cried more than six hours a day. I woke up all night and suffered a lot. The first six months of life I had severe anemia so they gave me 4 blood transfusions. By six months of age, I did not have anemia anymore, but the neutropenia continued. They gave me filgrastim or neupogen starting at the age of 3 months, as injections administered by my mother weekly. I traveled every month to another state and to the capital of the country to see the doctors. They knew that I had a bone marrow failure disorder, but in Mexico there is no genetic study to know what type of bone marrow failure I had.

My family organized raffles and fundraisers, so that we could pay for genetic testing. My sample was sent to the United States, and we learned that it was Shwachman Diamond syndrome, without mutation, the most common version, thank G*d. It took over 8 months or more until they understood that I did not have an allergy to cow's milk protein, but liver and pancreas problems, and a lot of lack of appetite due to the same syndrome, so I finally started using enzymes, Creon. It stabilized and we found the right dose, but not until I was a year and a half old.

They wanted me to have a bone marrow transplant at the best specialty hospital in the country, in the capital, but my mother felt in her heart that it was too aggressive to use it to prevent leukemia, and the cytomegalovirus could affect me. For a transplant, I don’t have any matches. We only had my father as a potential donor and that means only a 50% chance of success. They would not let us look for another donor, nor use an umbilical cord option, and they maintain that our best option would be my father. That is why we resumed fundraising, borrowed funds, and put in a lot of effort, so we could proceed with an online consultation with Boston Children’s Hospital, where there are specialists for Shwachman Diamond Syndrome. They explained to us that the transplant is only recommended if it meets the following requirements: continuous anemia and transfusions of blood, many serious infections, or cancer cells found in bone marrow biopsies. I “only” have neutropenia, problems with bone deformity in my chest, liver issues, and pancreatic insufficiency. Except for neutropenia, the latter issues would not change even after the marrow transplant. Boston explained to us that neupogen or filgastim are just rescue drugs when the child gets sick, not a long-term ongoing treatment, unless I get too sick (serious infections) or my neutropenia is very severe. That’s because every drug has side effects, and my shots could affect [stress my bone marrow cells], so that if leukemia is in my future, that could accelerate and develop sooner. We suspended the transplant plans because we finally understood the syndrome a little better.

My parents continue to take great care of me, and they try to make each day the best in the world, make me very happy and enjoy every day. I am a very sensitive and sweet boy, but I also love to laugh, run, and read books. We understood that having a rare disease does not define who I am. I am more than a disease - I am intelligent, affectionate, a unique human being, and that does not limit my happiness. I have a name, I am not just the sick relative or the sick child, I am very loved by my parents and family. In six months, I will be 4 years old. I am starting to have less panic with doctors, with people and life outside. Due to covid we continue with filgrastim. G*d willing, I hope we can soon stop the injections to see how my neutrophils can keep up, and experience life without this injection.

I have a page on Facebook (https://www.facebook.com/Leonardo.enfermedad.Shwachman.Diamond), TikTok (angel_leo_shwachmandiamond) and we have a support group on Facebook for Spanish speaking families from Latin America and beyond) (https://www.facebook.com/groups/844701606198176) all in Spanish to support families who are new to SDS, need support, or information and updates.

My parents taught me that apart from receiving help, I must also help. I have a big heart and I am a teacher of life for my family, a warrior and the best gift of life for my parents.

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<![CDATA[A Blast from the Past: Cresta's SDS Story from the US]]>https://www.sdsalliance.org/post/sds-story-cresta-usa6269d2b9dedbbecd81f8cbb4Wed, 27 Apr 2022 23:57:39 GMTEszter Hars, Ph.D., President and CEO, SDS Alliance"I look forward to many more years and to support research to aid SDS patients in the fight against leukemia and Myelodysplastic Syndrome." concludes Cresta. Read her and her family's story, here.

old photograph of Cresta as a toddler on her mom's lap

This is the Story of me: Cresta Morris. I have Shwachman Diamond Syndrome (SDS).

I was born and raised in Bend, Oregon. My parents, Ken & Celeste Harmon, had two other children with SDS: Mical (deceased in 1976) & and another girl (born in 1980). My parents were said to have been missing the same gene which would cause SDS in all three of their children. My sister Mical was 13 months when she died; it was revealed by an autopsy that she had died of Shwachman Diamond Syndrome. My Mom was 6 months pregnant with me when Mical died.

Three months after I was born my parents were told that I had SDS as well. At 11 months old, my parents tracked down Dr. Harry Shwachman himself and we flew to Boston to see him at Boston Children’s Hospital.

This in itself was a remarkable event. The whole community came together to make the trip possible for my family.

By that time, I had started exhibiting the same symptoms that my sister had before she died. My parents wanted to get answers – they wanted to know that I would be able to live. Dr. Shwachman put me on Cotazym (“Enzymes”) for food absorption/digestion for my pancreatic exocrine insufficiency (PEI). Dr. Shwachman told my parents the most important thing was for me to avoid contracting measles, mumps, pneumonia, or other serious illnesses and that if I made it to my 3rd birthday, the real big problems were over.

Dr. Shwachman told my parents the most important thing was for me to avoid contracting measles, mumps, pneumonia, or other serious illnesses and that if I made it to my 3rd birthday, the real big problems were over.

I just turned 46. My parents and I are so blessed to have each day. I made it past 3 years old and beyond. I am married and have 2 healthy girls. I work as an admin assistant at our local community college. I still have some health issues, but overall live a happy and full life.

I am of short stature: 5’1.5” (whereas my dad is 6’1” and mom is 5’8”); I take pancreatic enzymes (Creon) to aid in the digestion/absorption; I am on a dairy free diet, as dairy is hard for me to digest and entails profuse gas and stomach problems; I have neutropenia & low white blood cell counts; my bone marrow is being monitored closely; I have weak bones and issues with the bones in my knees and shoulder, plus recurring arthritis & cartilage issues.

In 2017, I was diagnosed with a squamous cell carcinoma on my tonsils which was treated successfully. That is how I found a doctor in Seattle, WA who specializes in SDS. Her name is Dr. Sioban Keel, a hematologist at Seattle Cancer Care Alliance. I go to Seattle once a year to see her for my annual bone marrow biopsy and to donate samples for SDS Research.

A casual current photo of Cresta
I look forward to many more years and to support research to aid SDS patients in the fight against leukemia and Myelodysplastic Syndrome.

Sincerely,

Cresta Morris

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<![CDATA[Mike's SDS Story from The Netherlands [Dutch and English]]]>https://www.sdsalliance.org/post/sds-story-mike-irma-netherlands6268741911d4b1e24965eadaTue, 26 Apr 2022 22:47:15 GMTEszter Hars, Ph.D., President and CEO, SDS Alliance"I hope to be able to support and help people where necessary with my story." Shares Mike's mom Irma. Read this Dutch family's story, here.

[Original language: Dutch]

Mijn naam is Irma van Dijk ,moeder van 2 kinderen waarvan van Mike (29 jaar)die geboren is met SDS.Wij wonen in Nederland.

Mike is 16 dagen te laat geboren met de navelstreng om zijn hals.47 cm en 2485 gram. Hij had een slechte start,maar mocht na 10 dagen in het ziekenhuis naar huis. Doordat hij niet groeide , dunne ontlasting en bacteriële infecties is hij met 9 maand gediagnosticeerd met SDS. Met 1,5 jaar kreeg hij sondevoeding.Dat heeft bijna 8 jaar geduurd. De eerste 4 jaren waren vreselijk,ziekenhuis in en uit.Longontstekingen en bacteriële infecties waren er constant. Door continu antibiotica ging dit beter.Voor de pancreassufficientie kreeg hij pancrease capsules.

Hij ging naar een school voor zieke kinderen in het lager en voortgezet onderwijs.

Door zijn autistisch gedrag is het nog steeds moeilijk om vrienden te maken en doordat hij niet erg zelfstandig is woont hij nog steeds bij ons. Mike heeft al sinds 7 jaar een vaste baan in de logistiek en heeft het erg naar zijn zin. Fijne collega’s en een werkgever met begrip voor zijn ziekte. Mike is nu 155 cm en vind dit lastig maar kan hier nu beter mee omgaan dan vroeger.

Hij rijd auto en dat is zijn passie.

Elke 2 jaar krijgt hij een beenmergpunctie,en om het half jaar wordt zijn bloed gecontroleerd. De controle’s in het ziekenhuis zijn nu ook minder dan vroeger.

Ik hoop met mijn verhaal mensen te kunnen steunen en helpen waar nodig.

[English translation]

My name is Irma van Dijk, mother of 2 children. One of them, Mike (29 years old), was born with SDS. We live in the Netherlands.

Mike was born 16 days late with the umbilical cord around his neck. 47 cm (18.5 inches) and 2485 grams (5.5 lbs). He had a rough start, but was allowed to go home after 10 days in the hospital.

He was diagnosed with SDS at 9 months of age due to lack of growth (failure to thrive), loose stools and bacterial infections. At 1.5 years he received a feeding tube. That lasted almost 8 years.

The first 4 years were terrible, in and out of hospital. Pneumonia and bacterial infections were constant. Continuous (prophylactic) antibiotics made this better. For the pancreatic insufficiency he was given pancreatic [enzyme] capsules.

He went to a school for [special ed] children in primary and secondary education.

Due to his autistic behavior it is still difficult [for him] to make friends. And because he is not very independent, he still lives with us. Mike has had a steady job in logistics for 7 years and is enjoying himself very much. Great colleagues and an employer who understands his illness.

Mike is now 155 cm (5.1 ft) [tall] and finds this [short stature] difficult but can now deal with this better than before. He drives a car and that is his passion.

He gets a bone marrow biopsy every 2 years, and his blood is checked every six months.

The checks-ups [and admission] in the hospital are now also less than before.

I hope to be able to support and help people where necessary with my story.

I hope to be able to support and help people where necessary with my story.
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<![CDATA[Dr. Eszter Hars chosen by The Milken Institute to join FasterCures LeaderLink Program]]>https://www.sdsalliance.org/post/milken-institute-fastercures-leaderlink6264659ba91aeb873e70d0aaSat, 23 Apr 2022 21:02:00 GMTEszter Hars, Ph.D., President and CEO, SDS Alliance

SDS Alliance’s President and CEO, Eszter Hars Ph.D., has been chosen by The Milken Institute to join the FasterCures LeadersLink Program. LeadersLink is a highly competitive program designed for patient-centered nonprofit leaders to find “faster cures” for their diseases. Dr. Hars was selected from a large, exceptionally well-qualified pool of candidates, as one of six LeadersLink winners, who will be provided access to a variety of expertise — from patient data resources to drug development — through the network of experts at the Milken Institute. Read more ,here.

“Advancing a promising scientific discovery to a viable treatment option requires long-term coordinated efforts from leaders across the biomedical ecosystem. Leaders from patient-centered nonprofits play a unique role in these efforts: they can leverage financial resources and data from the patient community to accelerate research that will have the most meaningful impact on patient lives — research that might not have progressed without their intervention.” says FasterCures

This year’s theme for the program is building patient data resources, which has been the focus of the SDS Alliance since its inception two years ago. As part of the LeadersLink program, Dr. Hars and SDS Alliance will further the SDS community's top priorities through a capstone project, mentorship, a series of in-person convenings, and virtual collaboration.

“I am incredibly grateful for this opportunity to work with The Milken Institute. The connections to the mentors and experts are priceless. It is a complex endeavor to find cures and we need to strategically leverage professional expertise every step of the way. I cannot wait to put all the new learnings into practice. As a community, we can move so much faster when we know exactly what to do and how to do it.” says Dr. Hars.

About the Milken Institute

The Milken Institute is a nonprofit, nonpartisan think tank that helps people build meaningful lives in which they can experience health and well-being, pursue effective education and gainful employment, and access the resources required to create ever-expanding opportunities for themselves and their broader communities. Our Approach: We catalyze practical, scalable solutions to global challenges by connecting human, financial, and educational resources to those who need them. We leverage the expertise and insight gained through research and the convening of top experts, innovators and influencers from different backgrounds and competing viewpoints to construct programs and policy initiatives. For more information, visit ,https://milkeninstitute.org/.

https://youtu.be/O2swibP0Xtw]]>
<![CDATA[SDS & Science Snapshots (2022-03-20)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-03-2062389b543cea075110d3bf4bSun, 20 Mar 2022 04:00:00 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: Report of a new variant in DNAJC21 associated with SDS like symptoms; Plus, new FDA Guidance on Patient-Focused Drug Development

Welcome to our weekly updates on all things SDS and Science. 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!

Report of a new variant in DNAJC21 associated with SDS like symptoms

As most of you are aware, over 90% of SDS is caused by bi-allelic mutations in the SBDS gene. We covered that it a recent Snapshots issue. However, there are a few other genes that are implicated in SDS. Except for EFL1, there is no consensus among the science and medical experts whether the syndromes caused by the other genes should be called classic SDS, or rather SDS-like syndromes. DNJC21 is one such gene. It is involved in the pathway of ribosome biogenesis, i.e. the making of active ribosomes. More specifically, it seems to play an important role in building the larger (60S) subunit of the ribosome, ensuring that the "exit tunnel", which is a specific part of it, is properly formed.

Just to give you a rough idea about the complexities involved in ribosome biogenesis - with a large set of proteins working together to make it happen - see this figure from Dr. Warren's article from 2018. No, don't memorize it! Just notice all the different proteins and steps involved in building the 60S large subunit alone.

Back to this week's publication news. Last week, a collaboration between researchers from Turkey, the US, and the UK identified a new mutation in DNAJC21 that seems to lead to an SDS-like syndrome. DNAJC21 has been implicated in SDS before. What is new here is that the new mutation is in a region of the protein that has previous not been known to be important in this pathway / ribosome biogenesis.

You can find the full article, below.

A novel missense mutation outside the DNAJ domain of DNAJC21 is associated with Shwachman-Diamond syndrome.

Alsavaf MB, Verboon JM, Dogan ME, Azizoglu ZB, Okus FZ, Ozcan A, Dundar M, Eken A, Donmez-Altuntas H, Sankaran VG, Unal E. Br J Haematol. 2022 Mar 17. doi: 10.1111/bjh.18112. Online ahead of print. PMID: 35298850

https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.18112

New FDA Guidance on Patient-Focused Drug Development

The U.S. Food and Drug Administration recently released guidance for industry and other stakeholders - Patient-Focused Drug Development: Methods to Identify What Is Important to Patients.

What is a Guidance?

"FDA guidances are documents that explain the agency’s interpretation of, or policy on, a regulatory issue. The FDA prepares guidances primarily for industry, but also for other stakeholders and its own staff, and uses them to address such matters as the design, manufacturing, and testing of regulated products; scientific issues; content and evaluation of applications for product approvals; and inspection and enforcement policies.

Although guidances are not legally binding, they show stakeholders one way to reach their regulatory goal. However, stakeholders are free to use other approaches that satisfy the relevant law and regulations. Recently, FDA published a report on how to improve the processes that make these important documents available." ~ says the FDA.

New Guidance:

Patient-Focused Drug Development: Methods to Identify What Is Important to Patients
Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders

This is a must-read for all stakeholders - including us - involved in the drug development process. You can download the entire document, here.

Thank you to the FDA and all the stakeholders involved in developing this guidance to improve the process and outcomes for patients in need of treatments.

Beyond just reading it, we are proud to share that we have co-signed a letter containing specific suggestions to improve the guidance -- to be more helpful for the patient advocacy community.

And to make this rather long document more palatable for all of you, several of our friends in the rare disease community came together to read it out loud for you all. Thank you Kif1A.org for putting it all together!

https://youtu.be/oCIY4v78-1c

https://youtu.be/oCIY4v78-1c

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

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<![CDATA[SDS & Science Snapshots (2022-03-13)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-03-13622e9aa0d9549e3c66293646Sun, 13 Mar 2022 05:00:00 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: New report this week about COVID and COVID-vaccine tolerance in SDS patients; Plus, what is HLA and a Haplo-transplant, inspired by a case report of a Haplo-transplant in Japan

Welcome to our weekly updates on all things SDS and Science. 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 report published last week about COVID and COVID-vaccine tolerance in SDS patients

The COVID-19 poses a significant risk to patients with various chronic medical conditions. It has been a big question since the beginning of the pandemic to what extent SDS patients are at risk, in particular as SDS can cause patients to be immunocompromised due to malignancy or bone marrow failure (BMF). Because patients with SDS can experience neutropenia due to BMF, they carry a higher risk for serious infections - at least bacterial origin - compared with the general population. In this new report, the authors investigate the incidence and severity of COVID-19 in the population of patients with SDS.

Participants in the North American SDS Registry received a survey in the summer of 2021. 73 participants responded. Answers were anonymous.

  • 10 participants experienced COVID-19 All participants who developed COVID-19 were symptomatic of infection, with the most common symptoms being respiratory, such as congestion or cough (70%), and fever (60%). The median duration of symptoms was 4.5 days. One of 10 patients required hospitalization, but did not require supplemental oxygen. Most reported having a short duration of symptoms that did not require hospitalization or result in serious virus-related complications.
  • 18 participants received a COVID-19 vaccine, and actually all of them received two mRNA vaccine doses. Arm pain was the most common side effect (66.7%), followed by fatigue (50%), fever and/or chills (38.9%), and muscle aches (33.3%). Five of the 18 recipients (27.8%) reported experiencing no side effects.

The authors conclude: "Most patients reported a short clinical course with few requiring COVID-19–directed therapy, and only one requiring hospitalization; none experienced significant complications or severe cytopenias. However, these results cannot be generalized to patients with more severe comorbidities, and the relatively small number of patients described limits our ability to comment on risk of developing serious COVID-19 compared with the general population"

Coronavirus disease 2019 and vaccination in patients with Shwachman-Diamond syndrome.

Galletta TJ, Loveless SK, Malsch MM, Shimamura A, Myers KC. Pediatr Blood Cancer. 2022 Mar 6:e29647. doi: 10.1002/pbc.29647. Online ahead of print. PMID: 35253346

https://onlinelibrary.wiley.com/doi/10.1002/pbc.29647

What is HLA? What is a Haplo-transplant?

Bone marrow or stem cell transplants are always on the mind of the SDS community, as SDS can make it necessary either due to causing bone marrow failure or MDS/leukemia. If it comes to that, many patients rely on the generosity of stem cell donors who sign up with special registries and volunteer to donate stem cells if a patient in need matches with their HLA type. However, many patients can't find a match.

More information about the need and donation process is available on our website, ,,here.

HLA stands for human leukocyte antigens. HLA are proteins—or markers—on most cells in the body. Our immune system uses HLA to see which cells belong in our body and which do not. These markers are critical for stem cell transplants. The closer the donor's and recipient's HLA type match (are the same), the more likely it is for the recipient to accept the new cells and the new cells not to cause complications (such as Graft versus Host Disease (GvHD)) in the recipient's body. That's why in preparation for a bone marrow transplant, the medical team performs a very thorough search and analysis of potential donors.

https://youtu.be/YVer3lUv6HQ

Unfortunately, many patients in need of a stem cell transplant don't have a suitable donor - a donor who's HLA type matches with theirs nearly identically - in their family or in the general population/ stem cell registries. The chances of this happening are particularly high in populations of ethnic minorities and mixed race patients.

This is where haploidentical matches/transplants are coming in. A haploidentical transplant is a type of allogeneic transplant. It uses healthy, blood-forming cells from a half- matched donor to replace the unhealthy ones. This is a type of allogeneic transplant where the donor matches exactly half of your HLA. A haploidentical, or half-matched, donor is usually the recipient's mom, dad, or child. Parents are always a half-match for their children. Siblings (brothers or sisters) have a 50% (1 out of 2) chance of being a half-match for each other. It’s very unlikely that other family members (like cousins, aunts or uncles) would be a half-match.

https://youtu.be/kvtL8No8Kfk

While haploidentical transplant is a newer type of transplant and carries a higher risk of complications such as GvHD or graft failure, it also has some advantages. In particular, because donors are usually a close family members, they are usually very willing to donate and can travel to the medical center where the recipient is, ensuring very fresh stem cells and reducing the chance of delays during transport. They can also be available to donated additional stem cells during recovery, if needed. In many countries, haplo-transplants are preferred due to much higher costs associated with unrelated donors. There are medical centers that specialize in haplo-transplants, and there are many active clinical trials ongoing to improve outcomes.

Another alternative are cord blood stem cells. We will cover that in another post.

This video covers both options in great detail.

https://youtu.be/Cz4oLVfA1mc
New case report of a haplo-transplant in an adult SDS patient

In the SDS community, we have only been aware of one successful haplo-transplant. But last week, a new case report from Japan has been published.

The authors describe their experience treating a 21-year-old male patient with SDS, diagnosed with SDS genetically, as an adult. He developed acute myeloid leukemia (AML) and received a hematopoietic stem cell transplantation from his father, who is human-leukocytic-antigen-haploidentical. The patient received standard conditioning chemotherapy, total body irradiation, and Graft-versus-host disease prophylaxis. Unfortunately, although the patient achieved a complete remission initially, AML relapsed a year later. He passed away of sepsis.

[Haploidentical stem cell transplantation for acute myeloid leukemia associated with adult-onset Shwachman-Diamond syndrome].Uemura Y, Hirakawa T, Matsunawa M, Kozuki K, Saiki Y, Takimoto M, Sano F, Watanabe K, Inoue Y, Arai A. Rinsho Ketsueki. 2022;63(2):94-98. doi: 10.11406/rinketsu.63.94. PMID: 35264508 Japanese.

This report highlights the importance of focusing our research on the prevention of AML and our advocacy efforts on early and wide reaching SDS diagnosis of patients.

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

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<![CDATA[SDS & Science Snapshots (2022-03-06)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-03-066224eba19ab262e0654307a8Mon, 07 Mar 2022 04:56:03 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: Genes involved in SDS, autosomal recessive inheritance, and what is a mutation vs. a VUS?

Welcome to our weekly updates on all things SDS and Science. 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 genes are responsible for SDS?

Our genomes are organized into 23 pairs of chromosomes, made up of very long stretches of DNA. Genes are shorter sequences on the DNA, and each gene encodes one specific protein. Usually, the name of the gene corresponds to the name of the protein. The gene responsible for over 90% of SDS cases is called SBDS (for Shwachman-Bodian-Diamond-Syndrome), and the protein it encodes is called the SBDS protein. It was discovered by Dr. Johanna Rommens and her team, and published in 2003. Since then, several additional genes have been implicated in SDS, namely DNAJC21, EFL1, and SRP54. This GeneReviews article provides a comprehensive overview. Each of these newer genes account for less than 1% of SDS patients.

For about 10% of patients who meet the clinical definition of SDS, no genetic cause has been found thus far. This means that they don't have mutations in any of the genes mentioned above, or have only one mutation (which would only make them carriers). Research is ongoing in several labs around the world to look for additional genes that could be responsible for SDS; and to find additional hard-to-find mutations in the known genes. For example, traditional sequencing techniques are not able to identify large deletions that could have removed parts of the chromosome that contain the SBDS gene, and the patient could appear to have only one mutation. To find such large deletions, specialized testing is needed. Also note, that Analysis of SBDS is complicated by the presence of a highly homologous pseudogene, SBDSP.

Please reach out to an experienced SDS specialist or geneticist if these challenges could be relevant to you. We can help you connect with one (email us at connect@SDSAlliance.org).

What does it mean to be a carrier, not a patient?

SDS is inherited in an autosomal recessive pattern. This means that in order for SDS to happen, both copies of the gene have to lose (or significantly reduce) their function through mutations or deletions.

Note: This is actually quite a unique situation is SDS: complete loss of SBDS is not compatible with life. Therefore, all "SBDS" SDS patients have a mutation that greatly reduces the amount of functional SBDS protein, but doesn't completely eliminate it. The splice site mutation c.258+2T>C you may have heard about, or seen in your own genetic reports, is the most common SBDS mutation and can still produce a very small amount of functional SBDS protein.

If one copy of the gene is normal (functional), than the cell can make enough protein to make up for the mutated copy of the gene, and the cellular function can be maintained without issues. That is why carriers typically don't show any SDS symptoms.

https://youtu.be/Nv6qUsKYodAhttps://youtu.be/_oVvTkjDm6g

What is a mutation vs. a VUS?

Both terms refer to a change in a gene, i.e. a change in the sequence of the 4 bases (A, C, T, G) that make up the genetic code. Our genomes are made up of billions and billions of base pairs of DNA. The majority of the sequence is the same across all humans, but a tiny amount differ (0.01%). That means, such a difference occurs once in every thousand letters of the genome on average. However, due to the negative connotation of the word “mutation,” the human genetics community has started to use a new term: “variant.” The term variant underlines the fact that not all variants are harmful.

Sometimes it can be difficult to tell whether a variant is harmful or harmless. The mass screening of genes is called Next Generation Sequencing (NGS). NGS genetic testing involves looking closely at the base sequence in our DNA code. When the DNA bases are changed, the gene may function differently.

Most variants are harmless and in fact make you unique. Some gene variants may even be beneficial, and can offer a benefit during evolution. For example, a variant could potentially increase our natural defense against some viruses. On the other hand, some gene variants can lead to genetic disorders, such as SDS. Based on their capabilities of causing disorders, variants are classified into five major categories:

  • Pathogenic
  • Likely pathogenic
  • Variants of uncertain significance (VUS)
  • Likely benign
  • Benign

When looking at a particular variant, it can be tricky to figure out into which category it belongs. The determination is usually made by testing laboratories based on various types of evidence. For example, if many patients with a particular disorder all have the same "variant" or "mutation", and the protein's function is well known, then researchers make the determination that is is pathogenic. This information is then available to the testing laboratories through specialized online databases, and scientific publications. If such information is not established for a particular variant, computer modeling and comparison of the sequence of the same gene in other organisms can provide good evidence. For example, if a change is detected in a region of the protein that is known to be critical for its function, then the variant may be "likely pathogenic". And/or if the change is in a region of the gene that is the same across multiple species, then that suggests that it is critical for the protein's function, and again is "likely pathogenic".

Unfortunately, more often then not, the above mentioned evidence is not present, and therefore scientist and clinicians don't have enough information to determine the significance of the variant. In those frequent cases, the variant would be called a VUS (variant of uncertain significance).

The best way to determine whether a variant is significant would be to develop a functional assay to determine whether the cellular process in which the protein is involved is disrupted; or whether some other key phenotype is affected. Another term for these measures are biomarkers, and as explained in a previous snapshots issue, they are incredibly important for therapy development as well. In the case of SDS, if there was an easy, validated assay to measure ribosome assembly or other markers, that would be a great way to tell whether a VUS in SBDS has any significance. We are currently working with our partners on develop biomarkers for this and other reasons.

Have you or your loved-one received VUSs in your genetic report? It’s important to work closely with an experienced SDS specialist or geneticist to help you understand what the VUS might mean for you or your family. Not all variants in SBDS or the other SDS genes means SDS. If a child is diagnosed with a VUS, it is helpful to have mom and dad tested as well to see if either of them have the same variant. If a parent shares a variant with their child, but the parent does not have symptoms that the child is experiencing, it is less likely that the VUS is pathogenic (or it would have likely affected the parent).

Every family with SDS as a potential diagnosis on their genetic report should reach out to an SDS specialist and enroll in a Registry and/or Natural History Study that covers your geographical area. Find a list, here: https://www.sdsalliance.org/sds-registries. Contact us at connect@SDSAlliance.org if you need additional guidance.

https://youtu.be/thh2HfZn7yMhttps://youtu.be/n0oNaWpHws4

Why do I need to know whether I or my loved-one has "genetic" SDS?

As mentioned above, over 90% of SDS patients have mutations in both copies of their SBDS gene. This group of patients have been most thoroughly studies, as this is where most data is available. As most of us are keenly aware, SDS in these patients causes a high risk of MDS/AML (leukemia). However, this risk has NOT been established in SDS patients without a known genetic cause (often referred to as "clinical" SDS patients, or SDS-like). A recent example of some amazing research was published last year by Dr. Shimamura's group, where acquired / somatic mutations were measured and summarized. We can cover the article in more detail another time. The article is available for download, here: https://pubmed.ncbi.nlm.nih.gov/33637765/

As we learn more over time, it is very possible that different types of SDS patients will benefit from different types of monitoring and treatment options. Perhaps one group will need frequent monitoring for leukemic transformation and clonal hematopoiesis, while the others may not need monitoring that often. One group may benefit from some types of treatment options, while others may need other options. The natural history of the different groups may be different as well, and could have implications on how clinical trials and comparator arms are structured. Regardless of what category of SDS you or your loved-one falls into, please consider participating in research, be it in registries or clinical trials in the future. Find a list, here: https://www.sdsalliance.org/sds-registries.

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<![CDATA[SDS & Science Snapshots (2022-02-27)]]>https://www.sdsalliance.org/post/sds-science-snapshots-2022-02-27621b9c973de031d25a50271fSun, 27 Feb 2022 18:35:14 GMTEszter Hars, Ph.D., President and CEO, SDS AllianceIn this issue: Ribosomes in Mitochondria. Therapies and Cures start with an Accurate Diagnosis - what are we doing about increasing the speed and access.

Welcome to our weekly updates on all things SDS and Science. 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 publication on Ribosomes in Mitochondria in Nature Communications, a collaborative project by Drs. Alan Warren and Michal Minczuk's teams.

Our cells contain many different organelles necessary for cell function and therefore, life. We in the SDS community are mostly focused on ribosomes, the organelles in the cells that are responsible for translating the genetic information on the mRNA into proteins. In SDS, there is a problem with building these ribosomes, because there is not enough of an essential component (the SBDS protein) that is involved in the complicated ribosome-assembly process. Typically, when we talk about ribosomes, we mean the ribosomes that are in the cytoplasm or on the endoplasmic reticulum, i.e. the ribosomes that are translating nuclear genomic information into most of the proteins present in our cells. But, our cells have in fact another set of ribosomes: ribosomes within another set organelles called mitochondria. The ribosomes in the mitochondria (a.k.a. mitoribosomes) are structurally different and responsible for translating genetic information encoded in mitochondrial DNA. These ribosomes are NOT involved in SDS, but can cause mitochondrial diseases if there is a defect. Mitochondria are organelles responsible for converting energy from food into ATP, the chemical energy our cells need to live and thrive. See the two videos below to learn more about mitochondria and their role in energy metabolism.

This current publication talks about very detailed work on how components of the mitochondrial ribosomes are modified and regulated. The article titled "A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit" can be downloaded, here: Nature Communications volume 13, Article number: 929 (2022).

https://youtu.be/39HTpUG1MwQhttps://youtu.be/rgC4hmNksAo

Tomorrow is Rare Disease Day 2022!

Watch out for our special edition ,newsletter (coming soon) with Rare Disease Day (and month) highlights!

Therapies and Cures start with an Accurate Diagnosis - what are we doing about increasing the speed and access.

Most of us in the rare disease community are painfully aware how difficult and long the process of getting a correct and accurate diagnosis can be. Hence the term "Diagnostic Odyssey".

Source: https://www.raconteur.net/infographics/the-diagnostic-odyssey/

The average time to a correct and accurate diagnosis is about 5 years, and requires visiting multiple specialist.

Source: https://rarediseases.org/new-patient-journey-infographic-gives-a-glimpse-into-the-diagnostic-odyssey/

For us at the SDS Alliance, increasing the efficiency of SDS and rare disease diagnosis is a top priority, because it will

  1. reduce the suffering of individuals and their families, enabling access to best treatments and support
  2. provide patients the opportunity to participate in natural history studies and voice their needs and priorities
  3. provide the opportunity to help in the therapy development process by participating in research and providing data and samples

And how are we approaching this? Because SDS is very rare, our strategy is to "ENABLE ACCIDENTAL DIAGNOSES". That is, instead of trying to educate a handful of specialists about SDS only, we are investing into

  • making sure SDS genes (in particular SBDS) is covered on as many diagnostic panels as possible, so that doctors can stumble upon SDS even if they don't think of specifically testing for it
  • educate current hematology, immunology, and GI specialist about rare disease in general, including SDS
  • changing how the next generation of doctors think about rare disease. You may have heard the saying: when you hear hoofbeats, think horses, not zebras. We need the medical community to be aware and consider zebras sooner and more widely, once they rule out horses. This will be a win-win for everyone involved.

More information on all our initiatives coming soon.

If you or your loved one already suspect SDS and needs help accessing diagnostic tools and provides, please reach out to us. We have identified resources anywhere in the world to help you with specialists and financial support, if needed. Email us at connect@SDSAlliance.org

Repeat: PubMed overview

What is PubMed.gov, you may ask? Check out this nice summary from McGill University.

The SDS research community is small, so we don't expect SDS specific scientific publications every week, and not every new publication is relevant. But if there are any good ones, we will cover them in this section of snapshot posts. If you need access to a full text article, and its not available through the PubMed link, we may be able to help you. Email us at library@SDSAlliance.org.

Here is a quick over view of what PubMed is and how it works.

https://youtu.be/ZAtP0x9eb0A

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