Journal
The clinical landscape for SMA in a new therapeutic era.
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene, provides for the first time a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.Spinal muscular atrophy is a genetic neuromuscular disorder, in which the mainstay of management is physiotherapy, respiratory care and nutritional support, measures which do not affect the underlying biological progression of the disease. The treatment of SMA has now fundamentally changed with the demonstration that nusinersen (Spinraza™), a drug which alters the way in which RNA is processed, can increase the amount of SMN, the protein that is missing from children with SMA. This prevents nerve-muscle connections degenerating and is effective in limiting the severity of the disease, allowing young children to reach developmental milestones which are never normally achieved in SMA. This is a major landmark in the treatment of neurological disease, but only the beginning of the path to making SMA definitively treatable. A number of problems must be solved, including how to deliver the drug efficiently into the brain and spinal cord without the need for a lumbar puncture. There is uncertainty as to whether nusinersen will work for older children and adults with SMA. Despite these unresolved issues the advent of the first effective treatment for SMA ushers in a new era of therapy for this devastating disease and offers hope for the treatment of other neurodegenerative and neuromuscular disorders.