Promoting expression in gene therapy: more is not always better.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by loss-of-function of . 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.

Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy.

The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA.