GHP May 2017

22 GHP / May 2017 , 1703GH09 An Academic Whose Research is Increasingly Turning to Drug Discovery The Icahn School of Medicine at Mount Sinai is an international leader inmedical and scientific training, biomedical research, and patient care. We invited Charles Mobbs, Professor, Neuroscience, Geriatrics and Adult Development, to talk us through his work and the secrets behind his success. Chartered as a medical school in 1963, the Icahn School of Medicine at Mount Sinai incorporates seven hospital campuses, and has more than 5,000 faculty and nearly 2,000 students, residents and fellows. Among these is Professor Charles Mobbs, an academic whose research is increasingly turning to drug discovery, especially for Alzheimer’s Disease and other neurodegenerative diseases such as Parkinson’s and Huntington’s. The prevalence of these diseases, especially Alzheimer’s Disease, is rapidly increasing due to the aging of the population throughout the world, a phenomenon projected to bankrupt the health system in 30-50 years unless effective pharmaceutical interventions are developed. This major commercial opportunity has not been lost on major and minor pharmaceutical companies alike, but so far despite billions of dollars invested in drug discovery and clinical trials, there has been little in the way of progress, and this poses opportunities for researchers such as Charles. He discusses his core goals and how he, with the dedicated support of his team, is working to achieve them. “Although it has always been my goal to discover drugs to treat age-related diseases, this only became feasible after about 20 years of basic research into the link between lifespan and age-related diseases. Initially, we focused on how dietary restriction increases lifespan and delays age-related diseases, with a particular focus on obesity and diabetes, but in the last few years have increasingly used models of proteotoxicity in both mice and C. elegans (and now EMRs in humans) to apply these results to drug discovery. “Central to my success is my team. These studies have taken many years to get to this point, and I have had many outstanding graduate students, post-docs, lab managers, and faculty colleagues who have made it possible. Thanks to their diligence and hard work, we have managed to secure funding from the NIH, many private foundations, and even a pilot drug discovery grant from Mount Sinai to support many of these studies.” The major challenge in developing drugs to treat Alzheimer’s and other neurodegenerative diseases is that drugs that successfully ameliorate symptoms in mouse models of these diseases are not effective in humans, except for a few extremely modest symptomatic treatments. Charles outlines the reasons for these challenges and explains how his team has created a new approach which helps to alleviate them. “According to my team’s hypothesis, there are two reasons for these failures: most mouse models are based on a narrow set of alleles, principally Abeta, Tau, and Presenilin, whereas actually Alzheimer’s may very well entail other unknown forms of proteotoxicity; and of course drugs can have different effects in mice and humans. We have therefore developed a novel approach to discovering drugs to treat Alzheimer’s Disease and other neurodegenerative diseases such as Parkinson’s and Huntington’s. “This unique approach involves high-throughput phenotypic screening of compounds for their impact on pathology in several different C. elegans models of proteotoxicity, then using Electronic Medical Records to assess likely applicability to humans. While it may seem unrealistic to discover drugs that are generally protective against multiple forms of proteotoxicity, in fact dietary restriction does produce such generally protective effects, and we have already discovered several compounds that are protective against multiple unrelated forms of proteotoxicity, some of which clearly mimic protective effects of dietary restriction. We have had several promising results using this approach, and continue further analysis. Obviously as an academic laboratory we can only take this so far and, at some point, will have to partner with major pharmaceutical firms to conduct clinical trials. We are currently exploring our intellectual property position with respect to several of our discoveries, so depending on how that is resolved we may be in a better position to partner with industry.” This future partnership, combined with the various developments the team’s research is set to uncover, will provide many great opportunities for new knowledge and understanding in this vital area of research, as Charles concludes. “Currently we are developing much more extensive screening approaches, including drug combinations, extensive dose- response studies, especially examining reversal of pathology, and examining mechanisms of protection using RNAi. Moving forward, these results will be combined with several different systems biology protocols, as well as EMRs, and extended to several mouse models of proteotoxicity, to develop novel compounds most likely to delay or reverse pathology in human neurodegenerative diseases.”