scholarly journals Gene therapy in spinal muscular atrophy : RNA-based strategies to modulate the pre-mRNA splicing of survival motor neuron

2008 ◽  
Author(s):  
Travis Baughan
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Mrna Splicing ◽  
Survival Motor Neuron

scholarly journals Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy

2020 ◽  
Vol 4 (1) ◽  
pp. e202000889
Author(s):  
Anne Rietz ◽  
Kevin J Hodgetts ◽  
Hrvoje Lusic ◽  
Kevin M Quist ◽  
Erkan Y Osman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Potential Drug ◽  
Transgenic Mouse Models ◽  
Fda Approval ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug–drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.

scholarly journals Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

2015 ◽  
Vol 4 ◽  
pp. 351-356 ◽  
Author(s):  
Nur Imma Fatimah Harahap ◽  
Dian Kesumapramudya Nurputra ◽  
Mawaddah Ar Rochmah ◽  
Ai Shima ◽  
Naoya Morisada ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Protein Degradation ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Protein ◽  
Motor Neuron Protein

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

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