Alagille Syndrome (ALGS)

Alagille syndrome (ALGS) is an uncommon genetic condition defined by complex patterns of multi-system organ involvement. Protheragen, a leading research service provider with decades of experience, has dedicated its expertise to unraveling the complexities of ALGS and pioneering innovative diagnostic and therapeutic solutions.

Overview of Alagille Syndrome (ALGS)

Alagille Syndrome (ALGS) can be defined as an uncommon disorder caused by genetic factors that follow the principle of autosomal dominant inheritance. Its phenotype includes multi-systemic involvement where the eyes, heart, skeleton, liver, face, kidneys, and blood vessels are the most commonly affected. Around 94 percent of cases are due to mutations in the JAG1 gene while NOTCH2 gene mutations are responsible for 2 to 4 percent of the cases. These mutations interrupt the normal function of the Notch signaling pathway which is essential for cell differentiation and organ growth. The features of ALGS can be strikingly different in the same family, creating challenges for diagnosis and treatment. The ALGS occurrence is estimated to be from 1 in 30000 to 1 in 50000 live births.

Fig.1 Mouse model of Alagille syndrome. (Andersson E. R., et al., 2018)

Diagnostics Development for Alagille Syndrome

Molecular Genetic Testing

Molecular genetic tests are crucial for diagnosing Alagille Syndrome. Identification of causative mutations is now usually done using next-generation sequencing (NGS) panels that focus on JAG1 and NOTCH2 genes. These panels permit concurrent testing of both genes which fortuitously enhances the diagnostic yield. If NGS fails to identify mutations, whole exome or genome sequencing is then performed to try and find other genetic variants. For instance, recent studies have reported mutation of JAG1 in the 26 exonic regions, further confirming the need for detailed genetic testing.

Therapeutics Development for Alagille Syndrome

• IBAT Inhibitors
  Maralixibat and odevixibat, considered IBAT Inhibitors, are an emerging drug class that may be useful in treating ALGS cholestasis. These drugs have been designed to block the IBAT, which lowers bile acids' intestinal absorption, and subsequently, the serum bile acid concentration. During the human trials, patients experienced a marked decrease in the sensation of itching together with lowered bile acid levels that improved their wellbeing. For example, maralixibat achieved sustained decreases in bile acids and itching for 48 weeks in phase 2b trials.
• RNA-Targeted Therapies
  RNA-targeted therapies such as anti-sense oligonucleotides (ASOs) and splice-switching small molecules can be developed to achieve JAG1 and NOTCH2 gene silencing. ASOs can effectively be synthesized to target and correct specific mutations by normalizing splicing and protein expression. For instance, in both the clinical and preclinical settings, eteplirsen, an ASO that targets the dystrophin gene in Duchenne Muscular Dystrophy, has shown positive results in changes in dystrophin protein levels. This same strategy could be used for ALGS by targeting certain mutations of the JAG1 or NOTCH2 genes.

Table 1. Current therapeutics and potential future therapeutics for ALGS. (Sanchez P., et al., 2021)

Disclaimer: Protheragen focuses on providing preclinical research service. 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.

Our Services

Protheragen is at the forefront of developing comprehensive diagnostics and therapeutics for Alagille Syndrome. Our services encompass state-of-the-art genetic testing, leveraging next-generation sequencing (NGS) panels to identify causative mutations in JAG1 and NOTCH2.

Diagnostics Development

• Karyotype Analysis Service
• Omics Analysis Service
• Biomarker Development Service
• Artificial Intelligence Service
• Customized Diagnostics Development

Therapeutic Development

• Small Molecule Drug
• Cell Therapy
• Gene Therapy
• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein
• Customized Therapy Development

Disease Models

• Jag1^H268Q (Jag1^Ndr/Ndr) Mouse Models
• Jag1^+/dDSL Mouse Models
• Conditional Jag1 Ablation in Portal Vein Mesenchyme Models
• Jag1/Notch2 Compound Heterozygous Mouse Models

Protheragen utilizes cutting-edge in vitro and in vivo models to study ALGS pathophysiology. Induced pluripotent stem cells (iPSCs) and organoid cultures derived from patient samples provide a personalized platform for drug screening and efficacy evaluation. Additionally, our animal models recapitulate key features of ALGS, allowing for preclinical testing of novel therapies. If you are interested in our services, please feel free to contact us.

References

• Andersson, Emma R., et al. "Mouse model of Alagille syndrome and mechanisms of Jagged1 missense mutations." Gastroenterology 154.4 (2018): 1080-1095.
• Ayoub, Mohammed D., and Binita M. Kamath. "Alagille syndrome: diagnostic challenges and advances in management." Diagnostics 10.11 (2020): 907.
• Sanchez, Phillip, et al. "Therapeutics development for alagille syndrome." Frontiers in Pharmacology 12 (2021): 704586.