Spinobulbar muscular atrophy (SBMA) is an untreatable degenerative disorder of motor neurons and skeletal muscle caused by a CAG/glutamine tract expansion in the androgen receptor (AR) gene. The polyglutamine AR (polyQ AR) undergoes hormone-dependent nuclear translocation and unfolding, steps that are essential to toxicity and to the development of progressive muscle weakness in men. Although the disease causing mutation was identified over two decades ago, mechanisms central to SBMA pathogenesis remain poorly understood. As an alternative to focusing on downstream pathways disrupted by the polyQ AR, here we propose to test a novel therapeutic strategy using antisense oligonucleotides (ASO) to knock-down expression of the mutant gene. The objective of this application is to complete preclinical studies in a knock-in mouse model of SBMA to establish the safety and efficacy of peripherally delivered ASO. Our central hypothesis is that toxicity of the polyQ AR in the periphery is an important contributor to disease pathogenesis and an attractive therapeutic target. This hypothesis, which is distinct from efforts in the field aime at targeting toxic effects within the CNS, is based on our preliminary findings using ASO that suppress AR gene expression in the periphery but not CNS following subcutaneous administration to mice. These ASO were developed in an on-going academic-industrial partnership with Isis Pharmaceuticals, a company that specializes in ASO production. Working with Isis, we found that peripheral gene suppression rescues deficits in skeletal muscle mass, muscle fiber size, and lifespan in a knock-in mouse model of SBMA developed by our laboratory. These data point to an important role of peripheral polyQ AR in disease and suggest a novel route to therapy. Using phenotypic, histological, genetic and biochemical analyses we will establish the optimal ASO delivery route, dose and time course to ameliorate disease in SBMA knock-in mice (Aim 1), and determine the long-term effects of peripheral ASO therapy (Aim 2). If successful, these studies will provide essential efficacy data in a preclinical mouse model, which will then proceed to lead optimization and IND-enabling studies in the next stage of this project, as a prelude to a clinical trial in human SBMA patients.
of the proposed studies to public health is that they will provide essential efficacy data in a preclinical mouse model of SBMA for ASO therapy. If successful, this project will proceed to lead optimization and IND-enabling studies as a prelude to a clinical trial in human SBMA patients.