Therapy development in spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is the predominant form of motor neuron disease in children and young adults. In contrast to other neurodegenerative disorders, SMA is a genetically homozygous autosomal recessive disease that is caused by deficiency of the survival motor neuron (SMN) protein. This homogeneity should in principle facilitate therapy development. Previous therapy approaches have focused on upregulation of SMN expression from a second SMN (SMN2) gene that gives rise to low amounts of functional SMN protein. Drug development to target disease-specific mechanisms at cellular and physiological levels is in its early stages, as the pathophysiological processes that underlie the main disease symptoms are still not fully understood. Mouse models have helped to make conceptual progress in the disease mechanism, but their suitability in the search for therapeutic agents remains to be validated--an issue that is ubiquitous to the translational therapeutic research of other neurodegenerative diseases. Human induced pluripotent stem cell technology for generation of large numbers of human motor neurons could help to fill this gap and advance the power of drug screening. In parallel, advances in oligonucleotide technologies for engineering SMN2 pre-mRNA splicing are approaching their first clinical trials, whose success depends on improved technologies for drug delivery to motor neurons. If this obstacle can be overcome, this could boost therapy development, not only for SMA but also for other neurodegenerative disorders.