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AAV5-miHTT Gene Therapy Demonstrates Sustained Huntingtin Lowering and Functional Improvement in Huntington Disease Mouse Models
- Source :
- Molecular Therapy-Methods and Clinical Development, 13, 334-343. CELL PRESS, Molecular Therapy. Methods & Clinical Development, Molecular Therapy: Methods & Clinical Development, Vol 13, Iss, Pp 334-343 (2019)
- Publication Year :
- 2019
-
Abstract
- Huntington disease (HD) is a fatal neurodegenerative disorder caused by an autosomal dominant CAG repeat expansion in the huntingtin (HTT) gene. The translated expanded polyglutamine repeat in the HTT protein is known to cause toxic gain of function. We showed previously that strong HTT lowering prevented neuronal dysfunction in HD rodents and minipigs after single intracranial injection of adeno-associated viral vector serotype 5 expressing a microRNA targeting human HTT (AAV5-miHTT). To evaluate long-term efficacy, AAV5-miHTT was injected into the striatum of knockin Q175 HD mice, and the mice were sacrificed 12 months post-injection. AAV5-miHTT caused a dose-dependent and sustained HTT protein reduction with subsequent suppression of mutant HTT aggregate formation in the striatum and cortex. Functional proof of concept was shown in transgenic R6/2 HD mice. Eight weeks after AAV5-miHTT treatment, a significant improvement in motor coordination on the rotarod was observed. Survival analysis showed that a single AAV5-miHTT treatment resulted in a significant 4-week increase in median survival compared with vehicle-treated R6/2 HD mice. The combination of long-term HTT lowering, reduction in aggregation, prevention of neuronal dysfunction, alleviation of HD-like symptoms, and beneficial survival observed in HD rodents treated with AAV5-miHTT supports the continued development of HTT-lowering gene therapies for HD. Keywords: Huntington disease, gene silencing, HD mouse model, gene therapy, therapeutic microRNAs, adeno-associated viral vector serotype 5
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
congenital, hereditary, and neonatal diseases and abnormalities
Huntingtin
lcsh:QH426-470
Transgene
Genetic enhancement
Mutant
Striatum
Article
Viral vector
03 medical and health sciences
gene silencing
0302 clinical medicine
Internal medicine
mental disorders
Genetics
medicine
Gene silencing
lcsh:QH573-671
Molecular Biology
business.industry
lcsh:Cytology
Huntington disease
HD mouse model
gene therapy
nervous system diseases
lcsh:Genetics
030104 developmental biology
Endocrinology
nervous system
030220 oncology & carcinogenesis
Molecular Medicine
therapeutic microRNAs
Trinucleotide repeat expansion
business
adeno-associated viral vector serotype 5
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy-Methods and Clinical Development, 13, 334-343. CELL PRESS, Molecular Therapy. Methods & Clinical Development, Molecular Therapy: Methods & Clinical Development, Vol 13, Iss, Pp 334-343 (2019)
- Accession number :
- edsair.doi.dedup.....aa3b564939eca57a4b425ae5bb8c85ab