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Precise design of JAK inhibitors may improve outcomes in variety of diseases

Mice engineered with a patient gene (JAK1 GOF: Neuron) show less lung inflammation, fewer immune cells, and reduced mucous production compared to controls. Image Credit: Kim et al., Cell.

A study from the Icahn School of Medicine at Mount Sinai in New York has reported some new insights into JAK inhibitors.

While current JAK inhibitors treat inflammation in conditions including eczema, the research suggests a need for a more nuanced approach to modulating JAK activity for disorders such as asthma. This mouse study indicates that enhancement, rather than inhibition, of JAK activity may open new avenues for therapeutic intervention, diverging from traditional JAK inhibitors that primarily target immune cells.

Published in the December 21, 2023, edition of Cell, the researchers used a mouse model with a patient-specific JAK1 gain-of-function (GOF) mutation, revealing the mechanism by which this mutant protein induces disease and its potential for broader therapeutic use. The JAK1 GOF mutation, initially reported by study co-author Dr. Stuart Turvey in 2017, is linked to immune dysregulatory and hypereosinophilic syndrome characterized by severe eczema and asthma. The JAK1 GOF mutation is a change in the gene that encodes the JAK1 protein, making it more active than normal. This increased activity can lead to overactive immune responses and may cause health problems such as autoimmune diseases or cancer.


This study demonstrated that activated JAK1 signalling exhibits tissue-specific effects, including an unexpected immunoregulatory role in lung sensory neurons that suppresses lung inflammation. 


“This may explain why JAK1-selective inhibitors, while highly successful in atopic dermatitis, have not advanced for asthma treatment, and implies that JAK1 signalling has varying or even opposing effects in different cell types and tissues,” lead author Dr. Brian Kim said in a press release. He is the Sol and Clara Kest Professor of Dermatology, Vice Chair for Research, and Director of the Mark Lebwohl Center for Neuroinflammation and Sensation at Icahn Mount Sinai. 


“Better understanding of JAK signalling in different parts of the body not only helps us discover new things about biology but also gives us a glimpse into how JAK medicines might be used in the evolving landscape of innovative treatments,” said Dr. Kim.

Added Dr. Turvey: “As a pediatrician, I started this work with a commitment to finding a diagnosis and treatment for a family where three members had severe eczema, asthma, and other allergic manifestations. It turned out that they were the first people in the world recognized to have a genetic change causing gain of function of JAK1.” He is Professor, Division of Immunology, Department of Pediatrics, Faculty of Medicine, and Canada Research Chair in Pediatric Precision Health, BC Children’s Hospital and The University of British Columbia, Vancouver.

“[This] publication, led by Dr. Kim and his team at Mount Sinai, is a powerful example of globally collaborative translational research where they started with this single family and have now generated fundamental insights into the interactions between the human immune system and the nervous system. This is precision medicine in practice.”


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