Neurodegeneration is an underlying cause of a number of disorders of the central nervous system, including Alzheimer's, Parkinson's and Huntington's disease (HD). Degeneration of neurons in these diseases is caused by toxic, misfolded proteins, which cause the neurons to be dysfunctional and ultimately to die. Drugs that protect neurons from the toxicity of these misfolded proteins might be effective in blocking disease progression. Autophagy is a key process for neuronal survival. It directs proteins to lysosomes for degradation and has a unique role in removing toxic misfolded proteins from cells. Since many proteinopathies, including HD, are caused by the build-up of toxic misfolded proteins, drugs that facilitate autophagy could remove disease- causing abnormal proteins from neurons to blunt neurodegeneration and disease progression. Nanosyn and the Gladstone Institute are partnering to develop novel neuronal autophagy-inducing drugs to treat HD and other neurodegenerative disorders. We discovered a class of structurally related compounds that effectively induce autophagy in striatal neurons, a primary site of neurodegeneration in HD. The prototypical drug of this series also prevented pathogenic mutant huntingtin from causing striatal neuronal degeneration in vitro, and some of the compounds in this series have been found effective in HD animal models. Structure-activity relationship analysis led us to develop a model pharmacophore of neuronal autophagy inducers. The pharmacophore provides the means to rationaly design a new family of neuroprotectants that are strong neuronal autophagy inducers, specifically designed to treat chronic neurodegenerative diseases, such as HD. In this Phase 1 SBIR grant, we will use rational drug design to identify unique compounds that optimally induce neuronal autophagy with improved potency;efficacy, safety and pharmaceutical properties over any previously identified drugs. This will involve use of standard medicinal chemistry and a virtual high-throughput screen (vHTS) of a directed 3 million compound library, a novel in vitro HD neuronal model, and automated HTS longitudinal assays that measure neuronal survival. Autophagy inducers will also be tested in human induced pluripotent stem cell-derived neurons made from HD patients to select compounds most effective in removing toxic proteins from clinically relevant cells. Autophagy induction will be measured using a unique in vitro HTS assay employing an optical labeling method to monitor intracellular traficking and turnover of LC3 in autophagosomes and an assay to measure autophagy induction in vivo in brain in GFP-LC3 mice. Lead compounds with optimized pharmacokinetics and brain availability will be tested for in vivo efficacy in the R6/2 and BACHD mice models of HD to establish preclinical efficacy. The drug most effective in both animal models will be selected for further development. These studies will provide the foundation for future Phase 2 studies to identify a clinical candidate to alow ultimately for human testing as a treatment for HD and possibly other neurodegenerative diseases.

Public Health Relevance

Nanosyn and the Gladstone Institute are devoted to the development of novel, safe and efficacious drugs to treat neurodegenerative disorders. In this grant application, we propose to develop drugs that induce neuronal autophagy to treat Huntington's disease (HD), a serious neurodegenerative disorder for which no treatment is available to prevent disease progression. Our goal in this grant is to optimize our neuroprotectants and subject leads to preclinical testing, including testing for efficacy in two animal models of HD which wil provide the foundation for Phase 2 studies that will involve standard IND enabling studies, including toxicology to begin clinical development of our neuronal autophagy inducers for treating HD and other neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Fertig, Stephanie
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Nanosyn, Inc.
Santa Clara
United States
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Barmada, Sami J; Serio, Andrea; Arjun, Arpana et al. (2014) Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 10:677-85