Alagille Syndrome
Alagille syndrome is a multisystem condition with a spectrum that ranges from life-threatening liver or heart disease. Some individuals appear to have only one feature, such as cardiac disease or aneurysm disease. As the leading global full-service provider focusing solely on rare cardiovascular disorder research, Protheragen is committed to providing full research and development services for complex diseases such as Alagille syndrome.
Introduction to Alagille Syndrome
Alagille syndrome is a highly variable multisystem disease, even occurring within affected members from the same family. The prevalence is approximately 1:30,000 to 1:50,000 live births. The phenotypic features of Alagille syndrome include bile duct hypoplasia on liver biopsy, cholestasis, congenital heart disease (principally pulmonary artery stenosis), butterfly vertebrae, and a distinctive facial appearance. Regarding cardiovascular findings, pulmonary vasculature (pulmonary valve, pulmonary artery, and its branches) is affected more frequently, and alterations are present in up to 94 % of individuals. The most common cardiac finding is pulmonic stenosis (peripheral and branch).
Fig.1 Vascular defects in the absence of Jag1. (Masek, J., and Andersson, E. R., 2024)Pathogenesis of Alagille Syndrome
Alagille syndrome is transmitted as an autosomal dominant trait. Inherited pathogenic variant in approximately 40% of individuals. Alagille syndrome is characterized by mutations in the jagged canonical Notch ligand 1 (JAG1) or in the receptor NOTCH2. The JAG1-Notch pathway plays a direct role in the development and homeostasis of the liver and vasculature, with profound effects on health. Disrupted Notch signaling causes defects in the formation of several organ systems, causing the distinctive features of Alagille syndrome.
Fig.2 Variety of symptoms in Alagille syndrome. (Ayoub, M. D., et al., 2023)Therapeutics Development for Alagille Syndrome
| Drug Name | Mechanism of Action | Targets | Research Phase |
|---|---|---|---|
| Maralixibat | Ileal bile acid transporter (IBAT) inhibitor; decreases reabsorption of bile acids in the ileum, increasing fecal excretion and lowering systemic bile acid levels. | IBAT | Approved |
| Odevixibat | Inhibitor of the ileal bile acid transporter, decreased systemic levels of bile acid. | IBAT | Approved |
| Atorvastatin | Through the inhibition of HMG-CoA reductase, resulting in a lowering of cholesterol synthesis. | HMG-CoA reductase | Phase IV |
| Gene Therapy | Seeks to correct the genetic error underlying JAG1, and has the potential to enhance cardiovascular development and function. | JAG1 | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a therapy plan recommendation. For guidance on therapy options, please visit a regular hospital.
Our Services
Protheragen has established a solid, scientific base to advance therapeutic drugs and meet the urgent needs of this research population using cutting-edge technologies. Our services include diagnostics and the entire pipeline of preclinical therapeutic development, for ease of move from early-stage drug discovery to application studies. Most importantly, our expertise carries over into disease models, and our focus is on developing and using in vitro and in vivo models that accurately reflect the disease phenotypes and enable robust drug efficacy testing.
Therapeutic Development Services
Diverse Platforms
Animal Model Development for Alagille Syndrome
Animal models are crucial for dissecting the underlying pathophysiology of Alagille syndrome, discovering new therapeutic targets, and proposing potential drugs and gene therapies. Our company focuses on state-of-the-art custom animal model development services for your preclinical research and drug discovery.
Genetically Engineered Animal Model
Animal models are engineered by manipulating key genes of Notch signaling in the development of Alagille syndrome, including in mouse and zebrafish, to recapitulate human disease phenotypes.
- Jag1 mutant model
- Other models
- Notch3 mutant model
In addition to our expertise in animal models, Protheragen's comprehensive services cover the essential pharmacokinetics and drug safety studies. Our pharmacokinetic services are focused on the analysis of drug ADME profiles. At the same time, our comprehensive drug safety evaluations, including toxicology and safety pharmacology testing, are intended to fully profile the safety of drug leads. And by providing this complete package of services, we enable our clients to accelerate the development of rare cardiovascular disease drugs with more confidence and alacrity. If you are interested in our services, don't hesitate to get in touch.
References
- Masek, Jan, and Emma R Andersson. "Jagged-mediated development and disease: Mechanistic insights and therapeutic implications for Alagille syndrome." Current opinion in cell biology 86 (2024): 102302.
- Ayoub, Mohammed D et al. "Management of adults with Alagille syndrome." Hepatology international 17.5 (2023): 1098-1112.
For research use only, not for clinical use.