The long term goal of this project is to identify splicing regulators that can be targeted by novel therapeutic approaches for the neurodegenerative disease, spinal muscular atrophy (SMA). SMA is a leading genetic cause of infant mortality. The disease results from homozygous deletion of the SMN1 gene, which codes for the survival of motor neuron (SMN) protein. Although the gene defect responsible for the disease is known, no cure or effective treatment for the SMA has yet been developed. There is an urgent need to identify cellular factors that can be effectively targeted for therapeutic benefit. Humans have a second gene, SMN2, that also codes for SMN protein, albeit at much lower levels due to a splicing defect resulting in skipping of exon 7 that results in the production of a truncated and unstable protein production from the SMN2 gene has been the focus of intense investigation as a promising target for SMA therapy. The objective of this project is to develop an approach to target defects in pre-mRNA splicing as a way to treat SMA. The central hypothesis of the project is that modulating regulators of SMN2 exon 7 splicing using decoy oligonucleotides will improve splicing and SMN protein expression for therapeutic benefit in SMA.
The specific aims towards achieveing these goals are to: 1) identify novel regulators of SMN2 exon 7 splicing and 2) develop decoy oligonucleotides approaches to manipulate regulators of SMN2 exon 7 splicing. These studies will give insight into the regulation of SMN2 exon 7 splicing and provide a novel approach to SMA therapeutics that can be translated to have broader impacts on other human diseases resulting from similar defects in RNA processing.
Spinal muscular atrophy (SMA) is a pediatric neurodegenerative disease for which there is currently no cure. The goal of this project is to identify novel cellular targets that can be manipulated for potential treatment of the disease. This project initiates studies to modulate cellular targets using a novel approach which could offer a therapeutic strategy for the treatment of SMA as well as other diseases with similar molecular defects.
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