In 1975, Dr. Daniel Alagille noticed that some of his young patients were suffering from cholestatic disease and shared symptomatic similarities involving the kidney, heart, and vertebrae. He was able to group these pathological characteristics under the umbrella of a disease that bears his name to this day: Alagille syndrome.
Alagille syndrome is inherited in an autosomal dominant manner and is caused by the dysfunction of the Notch signaling pathway. A hallmark of this disease is bile duct paucity, which causes cholestatic disease. Liver dysfunction then causes associated symptoms such as pruritis, xanthomas, as well as localized cholesterol and fat deposits. Mutations to Notch signaling also result in somatic manifestations, involving various organs such as the ones mentioned above.
A group of researchers sought to identify the current therapeutic developments in managing Alagille syndrome and published their work in Frontiers in Pharmacology. We will look at some of their findings in this article.
Let us first explore the mutation to Notch signaling in a bit more detail. “The Notch signaling pathway is a highly conserved and indispensable component of cell-cell based signaling,” the authors of the study wrote. In another study, Aster et al wrote, “Biochemical, cell biological, and structural studies from many laboratories have brought the details of the Notch signaling mechanism into focus over the past two decades.” Chief of this is the knowledge that it plays a vital role in biliary genesis during the development of the liver.
JAG1 (Jagged1) is a transmembrane ligand associated with Notch signaling. A mutation in one allele of the JAG1 gene is sufficient to cause the partial loss of the JAG1 protein. The mutation of JAG1 and the subsequent loss of functional JAG1 causes the reduction in cholangiocyte specification. This is enough to disrupt the normal development of bile duct development, resulting in the classic bile duct paucity commonly observed in Alagille syndrome.
Read more about Alagille syndrome etiology
NOTCH2 variants can also cause Alagille syndrome, but they are hardly ever the sole cause. Moreover, mutations in the NOTCH2 gene cause missense (68%) far more often than in JAG1 (15%).
If JAG1 is the main problem in Alagille syndrome, why not just inundate the patient with exogenous JAG1? Well, there are heavy risks involved. The authors of the review explained, “The introduction of high-levels of JAG1 can dramatically increase the risk of hyperplasia and cancer since cell-cell based contact inhibition and proliferation is greatly influenced by Notch signaling.”
Unfortunately, the currently available treatment options for Alagille syndrome are mostly highly invasive in nature, although there are attempts to create drugs that can address the symptoms of the disease and thus improve the quality of life of patients. A surgical treatment option is partial external biliary diversion (PEBD), which aims to reduce bile acids present in the blood. This treatment approach helps with pruritis and xanthomas, but may not be sufficient to avoid the need for liver transplantation later on.
In cases in which Alagille syndrome has progressed to end-stage liver disease, liver transplantation is the only treatment option left. However, patients with Alagille syndrome can sometimes deteriorate rapidly while being on the waiting list for a liver transplant. This accounts for the significant mortality rates among patients with the disease.
Read more about Alagille syndrome therapies
Highly invasive interventions are never without risk, whether it be PEBD or liver transplantation. In liver transplantation, long-term immunosuppressants can aggravate the kidney, often leading to the need for a kidney transplant—and having a double transplant weakens the patient considerably. However, liver transplantation is a necessity and not a luxury: transplant-free survival among Alagille syndrome patients to the age of 18.5 is at a mere 24%.
Maralixibat is a drug that has been recently approved by the FDA for cholestatic pruritis in Alagille syndrome patients 1 year of age and older. It works by inhibiting the apical sodium-dependent bile acid transporter (ASBT), a carrier protein also known as the ileal bile acid transporter (IBAT). ASBT is involved in the recirculation of about 95% of bile acids back to the liver. By inhibiting ASBT, maralixibat is able to treat cholestatic disease by reducing the return of bile acids to the liver.
A study involving maralixibat demonstrated that children taking the drug showed statistically significant improvement in pruritis and reduction in xanthomas, which improved the quality of life of the patients. Cholestatic pruritus, although just one of the various manifestations of Alagille syndrome, can be debilitating because it can cause relentless scratching (which does nothing to relieve the itch), leading to skin scarring and bleeding.
Gene therapy is a form of therapy that is currently under intense investigation. The adeno-associated virus (AAV) is known for its ability to deliver genes in vivo and is heralded as a promising method to deliver gene therapy. How it works is that recombinant AAVs (rAAVs) are produced with the therapeutic gene of interest replacing any pathological gene. This has led to the use of rAAVs in a number of genetic diseases, such as retinal dystrophy and spinal muscular atrophy type 1.
RNA-targeted therapies have also become the focus of research attention in recent years. Antisense oligonucleotides (ASO) can modulate the splicing of disease-causing target transcripts, and drugs incorporating ASO have already been developed for diseases such as Duchenne muscular dystrophy and spinal muscular atrophy.
How do RNA therapies fit into Alagille syndrome management? The authors of the study explained, “Similar backbone structures from these approved drugs could be used as a template for the creation of ASOs which modulate the splicing of JAG1 or NOTCH2 for specific mutations to restore the reduced JAG1-NOTCH signaling in ALGS.”
More Specific Targets
The exciting thing about the therapies mentioned above is that they offer physicians the means to target defective areas in a more focused manner. The authors of this review concluded that “it should be possible to generate RNA or gene-editing therapies for subpopulations of patients that carry mutations in the same region of either of these genes” and “to develop long-term or even permanent treatments that can be applied to all patients using rAAVs or nuclease-based gene editing.” This would go a long way from the current main treatment option of liver transplantation.
Sanchez P, Farkhondeh A, Pavlinov I, Baumgaertel K, Rodems S, Zheng W. Therapeutics development for Alagille syndrome. Front Pharmacol. Published online August 23, 2021. doi:10.3389/fphar.2021.704586
Aster JC, Pear WS, Blacklow SC. The varied roles of Notch in cancer. Annu Rev Pathol. Published online May 3, 2018. doi:10.1146/annurev-pathol-052016-100127