A study published in Science Advances shows very promising results for gene therapy treatment of neuromuscular conditions - and beyond.
Carlo Rinaldi, who led the research, explains:
"By performing deep transcriptomic analysis of human tissues, we have identified several naturally-occurring isoforms of the transcription factor Androgen Receptor (AR). One of these, AR isoform 2, attracted our interest because it is the most highly expressed, particularly in AR-responsive cell populations, such as motor neurons and skeletal muscle. Intriguingly, we found that this isoform, which encodes a truncated AR 45 kilodaltons in size (hence the name AR45), plays a fundamental role in biology by acting as a transcriptional decoy, fine-tuning AR activity by competitively occupying its DNA binding sites. Capitalising on this new knowledge, we delivered AR45 via recombinant adeno-associated virus (AAV) to a mouse model of spinal and bulbar muscular atrophy (SBMA), a genetic neuromuscular disease with high unmet clinical need, caused by mutations in AR by a mechanism of toxic gain-of-function. This strategy restored the altered transcriptional profile in affected tissues and strongly ameliorated the disease phenotype in mice, laying the ground for an innovative gene therapy approach."
Given the critical importance of AR transcriptional control in various diseases such as androgen insensitivity syndrome, benign prostatic hyperplasia, and prostate cancer, this isoform may potentially be a target for therapy not only for SBMA but also for other AR-related conditions.
Work currently underway in many laboratories to fully understand AAV biology and develop methods for improved delivery and manufacturing for human studies, will be absolutely critical to translate this and other promising gene therapy approaches into treatments for patients.