Genetic therapy for spinal muscular atrophy


235 Why motor neurons are the cell type most severely affected by loss of SMN has been a central conundrum in the field. Although many aspects of the molecular pathogenesis are still unclear, recent evidence points to a synaptopathy possibly devolving from a deficient presynaptic transcriptome, resulting in denervation and early motor neuron Unsurprisingly, in all metazoan species save humans, complete ablation of SMN is embryonically lethal. In humans, however, loss of SMN1 is offset by the presence of a variable number of copies of the human-specific gene SMN2, which makes a small amount of SMN protein, permitting initial survival of the organism but not of all motor neurons4. In the world of inherited pediatric disorders, the case of spinal muscular atrophy is particularly poignant. Most afflicted infants and children, while largely neurologically and completely cognitively intact, grow progressively weaker over time, with many ultimately succumbing to respiratory failure at a young age. Thus, research in this issue by Kaspar and colleagues1 reporting a gene therapy rescue of the disease phenotype in a mouse model of spinal muscular atrophy is welcome news—all the more so given the authors’ preliminary data suggesting that the approach could work in primates. This study, combined with the possibility of disease screening in newborns, raises, for the first time, hope of real therapeutic progress against this as yet untreatable disorder. The autosomal recessive 5q spinal muscular atrophies (so called as the disease gene maps to chromosome 5q13.1) are characterized by a loss of motor neurons, resulting in weakness of all volitional muscles and often an ultimately unsustainable respiratory failure2. Although the outlook for patients with spinal muscular atrophy type I, the most common and severe form of the disease, has improved with better nutritional and particularly better respiratory care (at least in the developed world)3, it is still one of the leading inherited causes of infant mortality. The genetics of 5q spinal muscular atrophy are complex. Instead of the discrete disabling intragenic mutations that underlie most recessive disorders, a portion or, most frequently, the entirety of the survival motor neuron (SMN)-1 gene is usually homozygously deleted. The ubiquitously expressed and evolutionarily conserved SMN protein is involved with many aspects of RNA metabolism. Genetic therapy for spinal muscular atrophy

DOI: 10.1038/nbt0310-235

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@article{Mackenzie2010GeneticTF, title={Genetic therapy for spinal muscular atrophy}, author={Alex E Mackenzie}, journal={Nature Biotechnology}, year={2010}, volume={28}, pages={235-237} }