Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT).
• Both full-length (FL) mutant HTT and a shorter, toxic HTT exon 1 protein (HTTexon1) from aberrant splicing contribute to HD pathology.
• Targeting both forms of mutant HTT may offer greater therapeutic benefit than targeting FL HTT alone.

Purpose of the Study:

• To evaluate the efficacy of an engineered microRNA targeting HTT exon 1 (miHTT) delivered via adeno-associated virus serotype 5 (AAV5) in reducing HTT1a mRNA and HTTexon1 protein in HD mouse models.
• To assess the impact of AAV5-miHTT on both FL HTT and HTT1a mRNA and protein levels in the brain.

Main Methods:

• Development of an engineered microRNA (miHTT) targeting the HTT exon 1 sequence.
• Delivery of miHTT using adeno-associated virus serotype 5 (AAV5) via intrastriatal administration in zQ175 knock-in and Hu128/21 mouse models of HD.
• Quantification of HTT1a mRNA and HTTexon1 protein levels in brain tissues and neuronal cultures post-treatment.

Main Results:

• AAV5-miHTT administration led to dose-dependent expression of miHTT in the brain.
• Significant reduction in both FL HTT and HTT1a mRNA levels was observed at 2 months post-injection.
• Mutant HTT and HTTexon1 protein levels were significantly decreased in the striatum and cortex of treated mice.

Conclusions:

• AAV5-miHTT gene therapy effectively reduces both FL HTT and pathogenic HTTexon1 levels in preclinical HD models.
• This dual-targeting strategy holds potential for additive therapeutic benefits in Huntington's disease treatment.
• Further clinical studies are warranted to explore the therapeutic potential of AAV5-miHTT for HD patients.