{"doi":"10.1002/cpt.3393","title":"From Challenge to Opportunity: How Shwachman–Diamond Syndrome Became a Promising Target for Therapy Development","abstract":"Rare diseases affect over 30 million people in the United States and 300 million globally, yet 95% lack FDA-approved treatments. Rare disease therapy development poses unique challenges and opportunities. Shwachman–Diamond syndrome (SDS) is emerging as a model rare disease due to its uniform genetics, robust molecular understanding, and mature research infrastructure—including de-risking through model development, regulatory engagement, patient community development, ICD-10 implementation, and data access, driven by the SDS Alliance—a research-focused patient advocacy organization. Rare disease connects us all. Every one of us knows someone impacted by one of over 10,000 rare diseases, which combined affect 300 million people globally and over 30 million people in the US—nearly 1 in 10. 95% of rare diseases have no FDA-approved treatments, but the tides are changing. Drugs that target rare diseases represent over half of all novel drugs and biologics approved by the FDA in recent years. This did not happen overnight or by chance. The Orphan Drug Act of 1983 and the relentless advocacy of leading rare disease organizations made this possible.1 Developing drugs for rare diseases poses unique challenges and opportunities. Beyond financial considerations, developers face hurdles such as recruiting enough patients for clinical trials, obtaining natural history data, and designing clinical trials that can convincingly demonstrate safety and efficacy to regulators and patients. Opportunities include new niche markets with substantial financial potential and the intangible rewards of bringing therapies to patients in desperate need, witnessing firsthand the life-changing positive impact on families and communities. Given the large number of distinct rare diseases and the high risks involved in therapy development, what makes a rare disease a compelling target for investment? The more that is known about the disease mechanism, the more that patients are connected, and the more that relevant research tools and infrastructure are developed, the better. But often it takes serendipity and time. Small molecule drugs developed for a common condition may be a great fit for a rare disease (drug repurposing) based on its mechanism of action. Modern gene editing tools open doors for addressing the underlying cause of rare genetic disorders. Precision medicine is the new frontier, offering hope not only to rare disease patients but to all of us. SDS is a rare genetic disorder that affects about 1:100,000 births, and thousands of people globally, many undiagnosed due to variable presentation of symptoms.2, 3 It impacts multiple organ systems and significantly increases the risk of leukemia, with poor outcomes.4, 5 By age 30, about 30% of SDS patients develop acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or severe bone marrow failure, often necessitating a hematopoietic cell transplant (HCT)—a high-risk procedure with uncertain long-term effects. The outcomes for AML in SDS patients are particularly grim.4 Other common symptoms include failure to thrive, pain, and malnutrition due to exocrine pancreatic insufficiency (EPI), elevated liver enzymes, respiratory issues, skeletal abnormalities, and cognitive delays.2, 3 The severity of symptoms varies widely from patient to patient, causing frequently missed or delayed diagnoses, and putting patients at risk for unnecessary suffering and life-threatening complications. Most cases of SDS are caused by pathogenic variants in the essential gene SBDS,6 typically inherited from unsuspecting carrier parents in an autosomal recessive pattern, or caused de-novo by gene conversion/recombination with an adjacent pseudogene, SBDSP1. The SBDS protein plays a critical role in ribosome biogenesis by catalyzing the displacement of eIF6 from the large ribosomal subunit, thereby allowing the large and small ribosomal subunits to join and form a working ribosome.6 Ribosomes are large protein complexes th","journal":"Clinical Pharmacology & Therapeutics","year":2024,"id":483572,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":431583,"name":"Lisa J. McReynolds","orcid":null,"position":1,"is_corresponding":false},{"id":1324648,"name":"E Hars","orcid":"0000-0003-3674-3562","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:07:33.718973Z","pmid":"39039619","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}