AAV5-miHTT Gene Therapy Demonstrates Sustained Huntingtin Lowering and Functional Improvement in Huntington Disease...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington disease (HD) is a fatal neurodegenerative disorder.
• It is caused by a CAG repeat expansion in the huntingtin (HTT) gene.
• The expanded polyglutamine repeat leads to a toxic gain of function in the HTT protein.

Purpose of the Study:

• To evaluate the long-term efficacy of AAV5-miHTT gene therapy in Huntington disease mouse models.
• To assess the impact of HTT lowering on neuronal dysfunction, aggregate formation, and survival.

Main Methods:

• Intracranial injection of adeno-associated viral vector serotype 5 expressing a microRNA targeting human HTT (AAV5-miHTT) into the striatum of Q175 HD mice.
• Assessment of HTT protein reduction, aggregate formation, motor coordination (rotarod test), and survival analysis over 12 months post-injection.
• Functional proof of concept in R6/2 HD mice.

Main Results:

• AAV5-miHTT demonstrated dose-dependent and sustained HTT protein reduction.
• Suppression of mutant HTT aggregate formation in the striatum and cortex was observed.
• Significant improvement in motor coordination and a 4-week increase in median survival were noted in treated R6/2 mice.

Conclusions:

• Long-term HTT lowering by AAV5-miHTT effectively reduces aggregates and prevents neuronal dysfunction.
• The therapy alleviates HD-like symptoms and improves survival in rodent models.
• These findings support the continued development of HTT-lowering gene therapies for Huntington disease.