PROTAC-Mediated Degradation of mHTT Aggregates Attenuates Neurotoxicity in Cellular and R6/2 Mouse Models of Huntington’s Disease

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the <i>HTT</i> gene, producing mutant huntingtin (mHTT) that misfolds into β-sheet-rich aggregates and drives neuronal loss. Current HTT-lowering strategies face challenges, including invasive delivery and nonselective suppression of wild-type HTT. Here, we report the development and synthesis of proteolysis-targeting chimeras (PROTACs) to selectively degrade aggregated mHTT. The lead compound, PROTAC <b>2'</b>, consists of a (pyridylvinyl)aniline aggregate-binding ligand linked via polyethylene glycol spacers to pomalidomide, an E3 ligase recruiter for cereblon. PROTAC <b>2'</b> selectively degraded mHTT aggregates without affecting wild-type huntingtin and significantly reduced mHTT-induced cytotoxicity in the cell model. LC-MS/MS analysis confirmed the blood-brain barrier (BBB) penetration ability of PROTAC <b>2'</b> following subcutaneous administration. In an R6/2 HD mouse model, continuous PROTAC <b>2'</b> delivery via osmotic pumps improved body weight, motor coordination, and survival, correlating with reduced mHTT aggregation and neuroinflammation in the brain. These results highlight the therapeutic potential of aggregate-selective degradation as a disease-modifying strategy for HD, providing a promising alternative to conventional HTT-lowering approaches and supporting the broader potential of PROTAC-based therapeutics for neurodegenerative proteinopathies.