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

TL;DR

This study shows that a new drug called PROTAC 2′ can selectively break down harmful mHTT protein clumps in Huntington’s disease, improving symptoms in both cells and mice.

Contribution

The development of a PROTAC that selectively degrades mHTT aggregates without affecting wild-type HTT represents a novel therapeutic approach for Huntington’s disease.

Findings

PROTAC 2′ reduced mHTT-induced cytotoxicity in cell models without affecting wild-type huntingtin.

In R6/2 mice, PROTAC 2′ improved motor function, body weight, and survival while reducing mHTT aggregation and neuroinflammation.

LC–MS/MS confirmed that PROTAC 2′ can cross the blood–brain barrier after subcutaneous administration.

Abstract

Huntington’s
disease (HD) is a fatal neurodegenerative disorder
caused by an expanded CAG repeat in the HTT 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 2′, consists of
a (pyridylvinyl)­aniline aggregate-binding ligand linked via polyethylene
glycol spacers to pomalidomide, an E3 ligase recruiter for cereblon.
PROTAC 2′ 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 2′ following subcutaneous administration. In an R6/2
HD mouse model, continuous PROTAC 2′ 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.

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