Spinal muscular atrophy: Where are we now? Current challenges and high hopes

Abstract Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness. It causes movement issues and severe physical disability. SMA is classified into four types based on the level of function achieved, age of onset, and maximum function achieved. The deletion or point mutation in the Survival of Motor Neuron 1 (SMN1) gene causes SMA. As a result, no full-length protein is produced. A nearly identical paralog, SMN2, provides enough stable protein to prevent death but not enough to compensate for SMN1's loss. The difference between SMN1 and SMN2 is due to different exon 7 alternative splicing patterns. SMA molecular therapies currently focus on restoring functional SMN protein by splicing modification of SMN2 exon 7 or elevated SMN protein levels. Nusinersen, an antisense oligonucleotide targeting the ISS-N1 sequence in SMN2 intron 7, was the first drug approved by the Food and Drug Administration. Risdiplam, a novel therapeutic that acts as an SMN2 exon 7 splicing modifier, was recently approved. All of these drugs result in the inclusion of SMN2 exon 7, and thus the production of functional SMN protein. Onasemnogene abeparvovec is a gene therapy that uses a recombinant adeno-associated virus that encodes the SMN protein. There are also experimental therapies available, such as reldesemtiv and apitegromab (SRK-015), which focus on improving muscle function or increasing muscle tissue growth, respectively. Although approved therapies have been shown to be effective, not all SMA patients can benefit from them due to age or weight, but primarily due to their high cost. This demonstrates the significance of continuous treatment improvement in today's medical challenges.