Activating Autophagy to Prevent Neurodegeneration and Extend Lifespan
The decline in proteostasis is a hallmark of age-related neurodegenerative diseases such as Alzheimer’s Disease. Autophagy is the process by which cells rid themselves of damaged or otherwise unnecessary material, which then moves to the lysosome and degrades. Pharmacologic enhancement of autophagy could help treat or prevent age-related conditions.
The current standard of care for Alzheimer’s disease (AD) is largely inadequate as there are no effective treatments against the disease and progressive cognitive decline. Decline in proteostasis is a hallmark of neurodegenerative diseases such as AD. While numerous clinical trials are testing compounds and biologics that affect one protein associated with AD, our approach targets all disease-associated proteins via autophagy enhancement, in order to improve neuronal resilience against the proteotoxic stress of aging. Enhancing proteostasis in neurons is expected to prevent cognitive decline by protecting neuronal networks necessary for healthy living.
Innovation and Meaningful Advantages:
The transcription factor TFEB preferentially enhances the expression of autophagy and lysosome-related genes. Employing a genome-wide RNAi screen in C. elegans we searched for modifiers of the nuclear localization of HLH-30/TFEB and identified Exportin-1 (XPO1) is a potent inducer of TFEB nuclear localization. Inhibition of XPO1 by gene silencing or by a small molecule inhibitor (Selinexor) results in nuclear localization of TFEB and enhanced autophagy and increased lifespan in C. elegans. In human-derived cell lines, XPO1 inhibition results in TFEB nuclear localization, enhanced autophagy, and lysosome biogenesis without affecting mTOR activity. Small molecule inhibitors of XPO1 have great potential as autophagy enhancers that could be developed to treat or prevent neurodegenerative disease.
Commercial Development: Current State and Next Steps:
Recent findings from our laboratory have established a new entry point to modulate TFEB and autophagy with the aim of using this approach against neurodegenerative diseases. We are working to develop and test new XPO1 inhibitors and determine their impact on autophagy in different neuronal cell systems and to validate their use in a murine Alzheimer’s disease model.
Our goal is to collaborate with biopharma partners/funders who can bring into play the developmental, translational, and financial resources needed to advance this technology through regulatory approval and into the commercial marketplace.
Louis Lapierre, PhD
Assistant Professor of Molecular Biology, Cell Biology, and Biochemistry
Brown Tech ID #2469
2020-06-16 US20200222410A1; published.
Silvestrini M, et al., Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan. Cell Reports. 2018 May 15; 23(7): 1915-1921.
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