For Researchers > Basic/Pre-Clinical Research > Movement Disorders > Preclinical Drug Discovery in SBMA and Polyglutamine Diseases

Preclinical Drug Discovery in SBMA and Polyglutamine Diseases

We have previously found that molecular chaperones promote the turnover of the mutant expanded polyglutamine androgen receptor in SBMA, suggesting a therapeutic avenue. As a part of an NINDS-sponsored consortium, we have performed a high-throughput drug screen and identified several FDA-approved drugs that mimic the effect of molecular chaperones on steady-state polyglutamine-expanded AR levels, i.e. they reproduce our findings with molecular chaperones, which act to solubilize and promote degradation of the mutant protein. Our assay was the formation of detergent-insoluble, macromolecular AR complexes, which represent the biochemical correlate to intracellular inclusions. We have previously shown these complexes to decrease in quantity in the presence of molecular chaperones.

We identified several candidate drugs that have the desired effect, and several others were identified by consortium collaborators. The drugs that most consistently showed decreases in macromolecular complexes without cellular toxicity were then assessed for efficacy in a cell model of SBMA using full-length AR. This cell assay most closely reproduces the molecular pathology of SBMA seen in our mouse model and seen in SBMA patients. One drug that came out of the consortium screen is the herbal compound celastrol. This compound looks particularly promising in a number of polyglutamine disease models, including our own, and we are now investigating its mechanism and preparing to test its efficacy in our animal model of SBMA.

A second compound that we are testing is a 5-alpha reductase inhibitor, dutasteride, which is used to treat benign prostatic hyperplasia. Based on our finding in the SBMA mouse model that surgical castration can partially restore motor function as well as levels of unphosphorylated neurofilament heavy chain in motor neurons, our hypothesis is that inhibiting the conversion of testosterone to dihydrotestosterone chemically could have therapeutic benefit in SBMA.

We have also begun testing a third compound, a rho-kinase inhibitor identified by Mark Diamond at University of California, San Francisco. Preliminary tests in a cell culture model suggests the compound could be promoting turnover of mutant proteins, and we are preparing to investigate its efficacy in the mouse model.