More collaborative Alagille research is needed, review study says
Better understanding of genetic mutations may help advance targeted therapies
More collaborative research is needed to better understand Alagille syndrome and to help overcome challenges related to diagnosing and treating it, according to a recent review study.
Particularly, scientists believe that research focused on how specific genetic mutations influence disease severity will help in the development of better targeted therapies that could reduce the need for liver transplants in Alagille patients.
“To gain a profound understanding of the molecular and genetic underpinnings of this multisystemic rare disorder, as well as to develop innovative drug development strategies, fostering collaborations across multiple centers and embracing a patient‐centric approach is imperative,” researchers wrote.
The review study, “Alagille Syndrome: Unraveling the Complexities of Genotype–Phenotype Relationships and Exploring Avenues for Improved Diagnosis and Treatment,” was published in Cell Biology International.
Alagille syndrome is a rare disease largely caused by mutations in the JAG1 gene (about 94% of cases) and NOTCH2 gene (up to 3% of cases). These mutations affect the Notch signaling pathway, which is involved in embryonic development, and are therefore believed to disrupt early organ development.
Alagille symptoms and their severity vary widely
Patients exhibit abnormalities in various organs, including the liver, heart, eyes, kidneys, blood vessels, and other tissues, although particular symptoms and their severity vary widely.
Liver problems are a hallmark of Alagille and are due to the toxic accumulation of the digestive fluid bile in the organ because there are fewer-than-normal bile ducts, or the series of tubes responsible for carrying bile out of the liver to the intestines. This can eventually lead to liver failure, where a liver transplant is the only treatment strategy.
There are no disease-modifying treatments for Alagille, and disease management relies largely on interventions to ease symptoms and improve life quality. Because many patients end up needing a liver transplant before adulthood, the disease is associated with high healthcare and related costs.
To summarize what is currently known about Alagille and the current challenges in its diagnosis and treatment, a duo of researchers in India conducted a review of the scientific literature.
“This review explores the complex genetic and clinical landscape of ALGS [Alagille syndrome], emphasizing the challenges in understanding [genetic-clinical] relationships due to its rarity and the lack of suitable research models,” the researchers wrote.
Among the more than 100 Alagille-causing mutations reported to date, there is a high variability in terms of type of mutation and their location in the genes, which likely impact their activity in different ways. Researchers haven’t been able to establish a good correlation between the specific mutation type and disease symptoms.
Family members who have same mutation can have different symptoms
Even family members who have the same mutation can have very different symptoms. This has also raised the possibility of genetic modifiers, or genes whose variations do not directly cause Alagille but modify the effects of JAG1 and NOTCH2 mutations. A variety of potential genetic modifiers in Alagille, including POGLUT1, SOX9, and THBS2, have been identified, but their exact role remains unclear.
“The variability in symptoms observed among family members creates a complex scenario where each case is unique, demanding a tailored approach to management,” the researchers wrote.
Ultimately, the researchers emphasized that a more thorough understanding of the genetic landscape of Alagille could lead to the development of better treatments. It could also help facilitate early, accurate diagnosis, which is challenging in Alagille because its symptoms are variable and may overlap with other liver conditions.
Because Alagille is rare, there are several barriers to understanding the disease and achieving optimal care. This includes the lack of “a comprehensive set of strict clinical guidelines for characterizing ALGS-associated clinical features and diagnosis,” adequate research models, and the presence of challenges in coordinating large-scale clinical studies, the researchers wrote.
The scientists believe collaborative, multicenter consortiums, designed to follow patients from diverse racial and ethnic backgrounds, could play an important role in overcoming such barriers.
Collaboration necessary to establish common database
“Collaborative efforts from research institutions and healthcare organizations are necessary to establish a common database where genetic, clinical, and demographic information from patients across diverse populations can be pooled and compared,” the researchers wrote.
They also noted preclinical studies designed to better understand disease mechanisms, identify biomarkers, and screen for potential therapeutic targets, as well as screening assays to investigate the effects of different genetic mutations, will also be key.
New therapeutic approaches are emerging from this type of research, such as gene therapies and antisense oligonucleotides, which aim to address, in different ways, the underlying genetic cause of the disease.
Overall, there is a need for “further research and collaborative efforts in the field to ensure accurate diagnosis, effective disease management, and the evaluation of therapies, ultimately advancing toward precise, personalized treatments for those impacted by this exceptionally rare yet clinically significant condition,” the researchers wrote.
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