Androgen receptor isoform for spinal and bulbar muscular atrophy

DISEASE CATEGORY: Neurology

INDICATION: Spinal muscular atrophy (SMA)
Viral delivery of an androgen receptor isoform could help treat spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, a form of late-onset SMA characterized by polyglutanine-encoding CAG triplet expansions in the androgen receptor gene. Transcriptomic screening of human iPS-derived motor neurons and post-mortem brain samples identified a 45 kDa androgen receptor isoform that is highly expressed in both SBMA patients and healthy controls. Biochemical experiments showed overexpression of this isoform downregulated androgen receptor-controlled gene expression by disrupting interactions between the androgen receptor and its transcriptional coactivator bromodomain containing 4 (BRD4), which suggested the isoform could disrupt pathogenic androgen receptor activity in SBMA. In a trangenic mouse model of SBMA expressing a form of the human androgen receptor with 100 glutamine residues, AAV delivery of the 45kDa androgen receptor isoform extended survival from 87 to 102 days, improved muscle performance as measured by the rotarod test and rear grip strength, and corrected dysregulated gene expression without detectable toxicity in organs...