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 REVIEW:Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development. RECENT FINDINGS:Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials. In 2016, the first treatment for SMA has been approved in the USA, an antisense oligonucleotide that increases full-length protein product derived from SMN2. The approval of a first treatment for SMA and the rapid advances in clinical trials provide the prospect for multiple approaches to disease modification. There are several other promising therapeutics in different stages of development, based on approaches such as neuroprotection, or gene therapy.
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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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Project description:Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.
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