Spinal muscular atrophy: therapeutic strategies.

OPINION STATEMENT: Spinal muscular atrophy is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The loss of alpha motor neurons in the ventral horn of the spinal cord results in progressive paralysis and premature death. There is no current treatment other than symptomatic and supportive care, although over the past decade, there has been an outstanding advancement in understanding the genetics and molecular mechanisms underlying the physiopathology of SMA. The most promising approach, from current trials, is the use of antisense oligonucleotide (ASOs) to redirect SMN2 translation and increase exon 7 inclusion in the majority of the RNA transcript, to increase the production of fully functional SMN protein. Recently, ISIS Pharmaceuticals Inc. (2855 Gazelle Court, Carlsbad CA 92010) reported an interim analysis from a multiple dose study in children with SMA between 2 and 14 years of age, using ASO therapy. The results indicated good tolerability at all dose levels, increases in muscle function in children treated with multiple doses of ISIS-SMNRx, and increase in SMN protein levels in cerebrospinal fluid (CSF) from both single and multiple dose studies. Studies in infants are ongoing in a few centers; soon other institutions may begin enrollment. Infants are fragile and their disease process may differ from the older SMA population. It is not known whether effective drug would best be given to SMA infants or older children. Other promising therapies are still in preclinical phases or early clinical phases. Gene therapy appears to be efficient in improving survival in a severe mouse model of SMA, though a better definition of the route of administration and of the safety profile of the viral vectors is needed before clinical administration is possible.