Promoting expression in gene therapy: more is not always better

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by loss-of-function of SMN1. SMA is characterized by degeneration of motor neurons in the spinal cord, leading to progressive muscle weakness and atrophy. One of three currently available treatments is onasemnogene abeparvovec, an AAV9-based gene replacement therapy. Despite its effectiveness in improving motor function in SMA patients, its long-term safety profile remains unclear and adverse events such as liver toxicity are common. This may be caused by high vector dose or supraphysiological levels of SMN, driven by its strong, ubiquitous promoter. In this issue of EMBO Molecular Medicine, Xie et al addressed this by replacing the promoter of a benchmark virus—equivalent to onasemnogene abeparvovec—by an endogenous SMN1 promoter. In a common mouse model of SMA, treatment with this 2nd generation vector restored SMN expression close to physiological levels across tissues, resulting in improved safety and efficacy. This approach holds promise for safer and more efficacious AAV gene therapy for SMA and other diseases.