Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA

• Published in: Neuroscience research Vol. 53; no. 3; pp. 241 - 249
• Main Authors: Wang, Yu-Lai, Liu, Wanzhao, Wada, Etsuko, Murata, Miho, Wada, Keiji, Kanazawa, Ichiro
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.11.2005
• Subjects: Animals; Body Weight - genetics; Corpus Striatum - metabolism; Corpus Striatum - pathology; Corpus Striatum - physiopathology; Disease Models, Animal; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene therapy; Genetic Therapy - methods; HD mouse model (R6/2); Humans; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - physiopathology; Huntington Disease - therapy; Huntington's disease; Injections, Intraventricular; Intranuclear Inclusion Bodies - genetics; Intranuclear Inclusion Bodies - metabolism; Intranuclear Inclusion Bodies - pathology; Male; Mice; Mice, Transgenic; Motor Activity - genetics; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Peptides - genetics; Peptides - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; Small interfering RNAs (siRNAs); Survival Rate; Transgenes - genetics; Treatment Outcome; Trinucleotide Repeat Expansion - genetics; HD mouse model (R6/2); Huntington's disease; Gene therapy; Small interfering RNAs (siRNAs)
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2005.06.021

Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD.