The study also found that lamivudine, a commonly used NRTI, inhibited inflammasome activation, implicated as a key driver of type 2 diabetes, restored insulin sensitivity in type 2 diabetic human cells and prevented development of insulin resistance in non-diabetic human cells.
Dr. Jayakrishna Ambati, lead author of the study and DuPont Guerry III Professor and Founding Director of the Center for Advanced Vision Science at the University of Virginia, said, "Effective prevention and treatment of diabetes have remained a challenge. Data from a huge cohort of people over many years and the results of our work with lamivudine suggest that less-toxic molecules based on already approved NRTIs could provide a breakthrough in diabetes treatment and even prevention."
This study follows a preclinical study led by Dr. Ambati in 2014 showing NRTIs were efficacious in macular degeneration (AMD) in non-human models. NRTIs, in addition to their anti-viral effects also inhibit activation of a specific part of the immune system, the inflammasome. Inflammasome activation is thought to promote many chronic diseases such as diabetes, macular degeneration, Alzheimer's disease and multiple sclerosis.
"The research reported today in Nature Communications has important implications for our drug development program where we are seeking to treat inflammasome-mediated diseases such as AMD, Alzheimer's disease and multiple sclerosis with our proprietary, low toxicity NRTI derivatives," said Dr. Paul Ashton, President and CEO of Inflammasome Therapeutics. "This study shows, in a very large clinical data set, the potential for inhibiting inflammasome activation to treat diabetes. It also indicates the response we might expect in clinical trials in our drug development program for other inflammasome-mediated diseases. We anticipate being in the clinic for another inflammasome-mediated disease in 2021."
Treating Inflammasome-Activated Disease with NRTIs
NRTIs have been shown to inhibit inflammasomes, part of the immune system that helps trigger and maintain inflammatory response. In some prevalent, progressive, diseases such as diabetes, Alzheimer's disease, multiple sclerosis and AMD, inflammasomes no longer appropriately self-regulate, and prolonged inflammasome activation is associated with progressive tissue damage and disease progression. Unfortunately, in addition to inhibiting inflammasomes and blocking viral replication, NRTIs cause mitochondrial toxicity, leading to significant side effects. Slightly modified forms of NRTIs (named Kamuvudines) have been shown to inhibit inflammasome activity but without detectable mitochondrial toxicity. Inflammasome Therapeutics has identified, licensed and is developing Kamuvudines to treat inflammasome-mediated disease.
Inflammasome Therapeutics (www.inflam.com) was founded by Jayakrishna Ambati, M.D. and Paul Ashton, Ph.D., in 2016 to develop therapies for prevalent, degenerative diseases. The company combines scientific excellence with proven development expertise and works to develop products via a mixture of licensing agreements and internal development. The company currently has collaboration agreements with Boehringer Ingelheim and the Bill & Melinda Gates Foundation.
Source: Inflammasome Therapeutics
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