Loss of motor function, a short lifespan, and high mortality rate make spinal muscular atrophy a rare yet deadly disease for infants and children. Combined with the fact that no viable FDA-approved treatment currently exists for the disease, SMA has one of the most dire unmet medical needs in healthcare today. New studies involving mice, however, are beginning to yield early therapeutic results.
A new study entitled “Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy” published in August issue of Science reports the discovery of chemical compounds that by selectively modulating the splicing of Smn2 reestablishes a functional SMN protein, thus posing a new promise of treatment for spinal muscular atrophy.
Spinal muscular atrophy (SMA) is the leading cause of infant death among genetic disorders. Mutations in the Smn1 gene (short for survival of motor neuron 1) cause a defective production of SMN1 protein, a key protein in motor neurons’ survival. Thus, decreasing levels of SMN1 led to progressive neuromuscular degeneration and respiratory impairments.
Humans carry, in addition to the Smn1 gene, a second related gene — the Smn2 – but due to a phenomenon known as alternative splicing that occurs in the mRNA, Smn2 produces low amounts and less stable SMN2 protein. However, since both Smn1 and Smn2 genes are expressed ubiquitously, reestablishing Smn2 would lead to functional SMN protein and treat patients.
In this study, the authors performed a chemical screening and identified a class of chemical compounds that by modulating Smn2 alternative splicing induces the production of a fully functional SMN2 protein. When these compounds were administered into a mouse model of severe SMA, the authors observed increased levels of SMN protein and restored motor neuron function. Additionally, these compounds increased life span in severe mice models of the disease. Notably, these compounds have limited effects on splicing of other genes. Thus, the authors suggest that SMN2 splicing modifiers can be a new therapeutic approach to treat SMA patients. Furthermore, drugs targeting splicing events represent a new exciting area that can be translated to other splicing diseases and possibly translated into therapeutics.