Advances in therapeutic development for spinal muscular atrophy.
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ABSTRACT:
SUBMITTER: Howell MD
PROVIDER: S-EPMC4356243 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
Advances in therapeutic development for spinal muscular atrophy.
Howell Matthew D MD Singh Natalia N NN Singh Ravindra N RN
Future medicinal chemistry 20140601 9
Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct S ...[more]
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Project description:Purpose of reviewSpinal muscular atrophy (SMA) is an inherited childhood neurodegenerative disorder caused by ubiquitous deficiency of the survival motor neuron (SMN) protein - the hallmarks of which are the selective loss of motor neurons and skeletal muscle atrophy. Here, we highlight recent progress in the understanding of SMA pathology and in the development of therapeutic approaches for its treatment.Recent findingsPhenotypic characterization of mouse models of the disease, combined with analysis of SMN restoration or depletion in a spatially and temporally controlled manner, has yielded key insights into the normal requirement of SMN and SMA pathophysiology. Increasing evidence indicates a higher demand for SMN during neuromuscular development and extends the pathogenic effects of SMN deficiency beyond motor neurons to include additional cells both within and outside the nervous system. These findings have been paralleled by preclinical development of powerful approaches for increasing SMN expression through gene therapy or splicing modulation that are now in human trials.SummaryAlong with the availability of SMN-upregulating drugs, identification of the specific cell types in which SMN deficiency induces the disease and delineation of the window of opportunity for effective treatment are key advances in the ongoing path to SMA therapy.
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