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Intraperitoneal delivery of a novel drug-like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy.
- Source :
-
Scientific reports [Sci Rep] 2019 Feb 07; Vol. 9 (1), pp. 1633. Date of Electronic Publication: 2019 Feb 07. - Publication Year :
- 2019
-
Abstract
- Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that causes progressive muscle weakness and is the leading genetic cause of infant mortality worldwide. SMA is caused by the loss of survival motor neuron 1 (SMN1). In humans, a nearly identical copy gene is present, called SMN2. Although SMN2 maintains the same coding sequence, this gene cannot compensate for the loss of SMN1 because of a single silent nucleotide difference in SMN2 exon 7. SMN2 primarily produces an alternatively spliced isoform lacking exon 7, which is critical for protein function. SMN2 is an important disease modifier that makes for an excellent target for therapeutic intervention because all SMA patients retain SMN2. Therefore, compounds and small molecules that can increase SMN2 exon 7 inclusion, transcription and SMN protein stability have great potential for SMA therapeutics. Previously, we performed a high throughput screen and established a class of compounds that increase SMN protein in various cellular contexts. In this study, a novel compound was identified that increased SMN protein levels in vivo and ameliorated the disease phenotype in severe and intermediate mouse models of SMA.
- Subjects :
- Animals
Brain drug effects
Brain metabolism
Disease Models, Animal
Injections, Intraperitoneal
Mice, Knockout
Muscular Atrophy, Spinal mortality
Neuromuscular Junction drug effects
Severity of Illness Index
Spinal Cord drug effects
Spinal Cord metabolism
Survival of Motor Neuron 1 Protein genetics
Muscular Atrophy, Spinal drug therapy
Muscular Atrophy, Spinal etiology
Survival of Motor Neuron 1 Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 30733501
- Full Text :
- https://doi.org/10.1038/s41598-018-38208-9