Gene Mutation
SDS is mainly caused by mutations in the SBDS gene, which results in truncated, non-functional SBDS protein and affects ribosome assembly and function.
Shwachman-Diamond syndrome (SDS) is a rare disorder that poses a significant threat to human health. Protheragen has a gifted group of researchers and scientists with vast experience in SDS. They are dedicated to meeting therapeutic goals in SDS by developing modern therapies and pioneering work in targeted therapeutics for systemic illness.
Shwachman-Diamond syndrome (SDS) is an unusual condition that occurs due to mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. These mutations result in defective ribosome biogenesis and multi-system manifestations, including bone marrow failure, pancreatic exocrine insufficiency, skeletal dysplasia, and increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
Fig.1 Pathological mechanism of Shwachman-Diamond syndrome (SDS). (Reilly, Christopher R. and Akiko Shimamura., 2023)
Shwachman-Diamond syndrome (SDS) is essentially a ribosomopathy caused by mutations in the SBDS gene that disrupt the maturation of the ribosomal 60S subunit. The molecular pathogenesis involves:
Gene Mutation
SDS is mainly caused by mutations in the SBDS gene, which results in truncated, non-functional SBDS protein and affects ribosome assembly and function.
Ribosomal Biogenesis Defect
The non-functional form of the SBDS protein inhibits the maturation process of the 60S pre-ribosomal subunit and prevents the assembly of active 80S ribosomes. This hinders overall protein translation, most notably the translation of proteins essential for rapid cellular growth.
Because of the progressive course of Shwachman-Diamond syndrome (SDS), early management is essential. To date, available treatments continue to be mainly supportive and do not resolve the primary genetic problem. There is an important gap in the therapeutic options available to affected individuals as there are no disease-modifying therapies using the basic defect in the SBDS gene or ribosomal dysfunction as a target, which need to be addressed.
| Therapy | Targets | Mechanism of Action | Development Stage |
|---|---|---|---|
| Gene Therapy | SBDS gene | Viral vector-mediated delivery of functional SBDS gene to correct genetic defect | Preclinical |
| Eltrombopag | Thrombopoietin receptor | Stimulates megakaryopoiesis to increase platelet production | Clinical (phase II) |
| Tamibarotene | RARα receptor | Prevents MDS/AML progression | Discovery phase |
| L-Leucine | mTOR pathway | Enhances translation efficiency in ribosomopathies | Clinical |
| SBDS Protein Replacement | Ribosome assembly | Direct replacement of defective SBDS protein to restore ribosome maturation | Preclinical |
| EIF6 Inhibitors | Eukaryotic initiation factor 6 | Promotes 60S ribosomal subunit maturation by facilitating eIF6 release | Discovery phase |
| Rigosertib | PI3K and PLK pathways | Targets malignant clones in MDS/AML transformation | Clinical (phase III) |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Protheragen is committed to delivering unparalleled diagnostic and therapeutic development services tailored specifically for Shwachman-Diamond syndrome (SDS). Our expertise extends to the development of cutting-edge disease models that drive preclinical studies into potential therapies. With a focus on innovation and precision, we empower our clients with advanced solutions that pave the way for effective intervention strategies.
Genetically engineered models for SDS are created by introducing specific genetic mutations associated with SDS into animal models using gene editing techniques.
Specializing in preclinical research for drug development, Protheragen offers a comprehensive solution that includes pharmacodynamics (PD), pharmacokinetic (PK) and toxicology studies to thoroughly validate and optimize therapies for Shwachman-Diamond syndrome (SDS). If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
Reference
Myeloproliferative Disorders (MPDs)
Bone Marrow Failure Syndromes (BMFS)