systemic-delivery-microrna-using-recombinant-adeno-associated-virus

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents

RNA interference via the endogenous miRNA pathway regulates gene expression by controlling protein synthesis through post-transcriptional gene silencing. ...

National Institutes of Health

Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins.

Naemeh Pourshafie

Neurogenetics Branch,
National Institute of Neurological Disorders and Stroke,
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke

National Institutes of Health

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents

Naemeh Pourshafie

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Neurogenetics Branch,National Institute of Neurological Disorders and Stroke,Neurogenetics Branch, National Institute of Neurological Disorders and Stroke

National Institutes of Health

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents

Neurogenetics Branch,
National Institute of Neurological Disorders and Stroke,
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke