Translational Development and Mechanistic Characterization of Small Molecule Drug for Huntington's Disease Therapy - ABSTRACT: Translational Development and Mechanistic Characterization of Small Molecule Drug for Huntington’s Disease Therapy Huntington’s Disease (HD) is an inherited neurodegenerative disorder causing progressive motor and cognitive decline, along with behavioral and psychiatric disturbances. Symptoms typically appear around age 45, and after onset, the disease proves fatally debilitating within 15-18 years. The gene linked to HD, located on chromosome 4, leads to mutant huntingtin (mHTT), featuring an expanded trinucleotide repeat in HD patients. The expanded polyglutamine stretch due to the CAG repeat leads to abnormal interactions with other cellular proteins and contributes to HD's progression. Presently, a cure for HD remains elusive, and the existing treatments primarily focus on alleviating symptoms and managing disease progression, albeit with limited efficacy. Therefore, new approaches for the treatment of HD are urgently needed. In our pursuit of a potential therapeutic for HD, we employed an innovative in-silico fragment scanning technique, focusing on the mutant huntingtin (mHTT) polyQ surface, which led us to identify GLYN122 as a promising candidate. In vitro experiments demonstrated GLYN122's direct binding and reduction of mHTT levels, accompanied by neuron-inducing autophagy. Transitioning to in vivo studies, we validated GLYN122's ability to pass the blood-brain barrier, subsequently decreasing mHTT levels in the cortex and striatum of the R6/2 mouse model, resulting in improved motor symptoms. These compelling findings underscore the viability of GLYN122 as a prospective treatment for HD. We employ two genetic mouse models, YAC128 and HdhQ150, strategically chosen to comprehensively assess GLYN122's efficacy. These models, which collectively replicate aspects of human Huntington's disease, offer a more accurate approximation of human pathology. YAC128 mirrors motor deficits, while HdhQ150 demonstrates cognitive deficits before motor symptoms. In proposed studies, we will evaluate the therapeutic impacts of GLYN122 on motor deficits and neuropathological features within in vivo HD models. Additionally, we will conduct mechanistic investigations into the effects of GLYN122 on gene expression and transcriptional regulation in the context of HD. Finally, we will focus on the lead optimization of small molecule candidates through ligand-based virtual screening and rational design to enhance pharmacokinetics, oral bioavailability, and efficacy. The potential outcomes of the proposed studies hold great promise. If successful, GLYN122 has the potential to revolutionize the treatment of Huntington's disease by effectively addressing both its motor deficits and neuropathological features. Beyond the immediate benefits to patients, these studies could significantly advance our understanding of the mechanisms underlying HD and open new possibilities for therapeutic approaches. Additionally, the improved bioavailability of GLYN122 may lead to more convenient treatment administration for patients. Successfully completing this project not only has the potential to improve the quality of life for individuals with HD but also to have a broader impact on neurodegenerative disease research.
