Evaluation of Ferroptosis Inhibitors as Therapeutic Agents for Huntington’s Disease
Huntington’s disease (HD) is an autosomal neurodegenerative disease caused by the expansion of CAG repeats in the Huntingtin gene, resulting in the production of pathogenic protein with an extended polyglutamine tract that is prone to aggregation. Current therapeutic options for HD are limited, focusing solely on symptom management, with the anti-choreic drugs tetrabenazine and deutetrabenazine the only FDA-approved therapeutics for HD. As such, there is an unmet demand for therapeutics for HD. Ferroptosis is an iron-dependent, non-apoptotic, regulated form of cell death characterized by the lethal accumulation of lipid peroxides and lipid peroxide byproducts. HD is associated with glutamate toxicity and neurotoxicity, dysregulated polyunsaturated fatty acid metabolism, elevated iron, and lipid peroxidation, all of which are drivers of ferroptosis. The goal of the present study was to evaluate and screen novel ferroptosis-specific inhibitors as therapeutic agents in a mouse model of Huntington’s disease. These efforts were directed into two aims: the first, evaluating the mechanism by which the cardiovascular drug probucol likely inhibits ferroptosis; and second, testing analogs of the canonical ferroptosis inhibitor ferrostatin-1 (fer-1) in vitro and in vivo for their pharmacokinetic and pharmacodynamic profiles. This research has identified a potential new mechanism by which probucol inhibits ferroptosis that is independent of fer-1. Ongoing efforts have been focused on elucidating the components of the inhibitory pathway, providing a potential new area of therapeutic development for ferroptosis inhibitors. This research has also identified new, potent analogs of fer-1 that are stable in vivo and preferentially accumulate in the brain of mice. These results lay the groundwork to evaluate the efficacy of ferroptosis inhibitors in mouse models of Huntington’s disease to determine whether ferroptosis inhibition is a therapeutic strategy for HD
Receiving a Predoctoral Fellowship in Pharmacology/Toxicology from the PhRMA Foundation is a great honor that has had a profound impact on my current and future career prospects. This funding has allowed me to pursue novel hypotheses that can expand the current knowledge surrounding both ferroptosis and Huntington’s disease and could have a profound impact on individuals with Huntington’s disease. I am sincerely grateful to the PhRMA Foundation for its support in these efforts.