Study: Systemic Delivery of MicroRNA

István Reinhardt emailed me a link to a recent Kennedy’s Disease (SBMA) study. The video is also interesting. Clink on the link below to go to the site or download a PDF copy of the study with this link:  https://www.jove.com/pdf/55724

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

ABSTRACT

RNA interference via the endogenous miRNA pathway regulates gene expression by controlling protein synthesis through post-transcriptional gene silencing. In recent years, miRNA-mediated gene regulation has shown potential for treatment of neurological disorders caused by a toxic gain of function mechanism. However, efficient delivery to target tissues has limited its application. Here we used a transgenic mouse model for spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR), to test gene silencing by a newly identified AR-targeting miRNA, miR-298. We overexpressed miR-298 using a recombinant adeno-associated virus (rAAV) serotype 9 vector to facilitate transduction of non-dividing cells. A single tail-vein injection in SBMA mice induced sustained and widespread overexpression of miR-298 in skeletal muscle and motor neurons and resulted in amelioration of the neuromuscular phenotype in the mice.

In a 2011 post, Ed Meyerthoen explained the defective AR gene. You can read his post by following this link:  https://kennedysdisease.blogspot.com/2011/05/what-is-ar-and-why-is-it-important.html

MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Kennedy's Disease

Below is a link to research on Kennedy's Disease that was published in January in Molecular Therapy.

MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy

 Naemeh Pourshafie, Philip R Lee, Ke-lian Chen, George G Harmison, Laura C Bott, Masahisa Katsuno, Gen Sobue, Barrington G Burnett, Kenneth H Fischbec¹ and Carlo Rinaldi

Abstract

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.

 Follow the above link for the entire article.