Monday, April 28, 2025
4/28/2025
Novel treatment for Huntington???s Disease - DESCRIPTION (provided by applicant): Because of their degeneracy and selective involvement in most cellular pathways, ubiquitin conjugating and deconjugating enzymes are being explored as therapeutic targets for treating many major diseases, including neurodegenerative disease. The proteasome-associated deubiquitylase (DUB) USP14 plays a key role in regulating proteasomal degradation of pathogenic proteins such as tau, TDP-43 and ?-synuclein. Huntington's disease (HD) is a progressive, fatal neurodegenerative disease initially characterized by chorea and gait disturbances. The causative factor is accumulation of polyglutamine (poly Q) expanded huntingtin (Htt) protein, which is polyubiquitylated, but accumulates in inclusion bodies (IBs), rather than being degraded by the proteasome. Results from in vivo models link enhanced degradation of poly Q expanded Htt with reversal of behavioral deficits. Since USP14 has been shown to inhibit degradation of pathogenic, neurotoxic proteins, it is hypothesized that inhibitors of USP14 will accelerate Htt degradation, alleviating HD symptoms. Initial drug discovery around USP14 has not led to efficacious inhibitors, likely owing to both the inherent difficulty in assaying USP14 activity and a lack of cellular models for neurodegenerative disease for testing of hit compounds. These issues are addressed in the current application in two specific aims. In the first aim, two novel assay technologies will be employed to identify developable inhibitors of USP14. Primary screening (of Progenra's collection of 200,000 small molecules) will be conducted using thermal shift, a label free, high throughput-compliant biophysical assay format. Hits from this screen will be confirmed in a proprietary orthogonal assay of USP14 catalytic activity. After additional biochemical testing the compounds will be evaluated further (second aim) in newly developed breakthrough automated, longitudinal single cell imaging models that enable determination, in individual primary neurons, of the half-lives of proteins such as Htt over periods of hours or days. Powerful statistical modeling software developed to monitor clinical trials, applied to these data, will determine the overall risk of cell death following a defined perturbation (e.g., addition of USP14 inhibitor to cells expressing poly Q expanded Htt). These highly predictive models will be employed to determine the impact of novel USP14 inhibitors on both the half-life of poly Q-expanded Htt and proteasomal flux in primary neurons. The goal is to find a potent, selective small molecule inhibitor of USP14 which accelerates pathogenic Htt clearance in neuronal models of Huntington's disease.
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