Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy
Cathleen M. Lutz,Shingo Kariya,Sunita Patruni,Melissa Osborne,Don Liu,Christopher E. Henderson,Darrick K. Li,Livio Pellizzoni,Rojas Jose F,David M. Valenzuela,Andrew J. Murphy,Margaret L. Winberg,Umrao R. Monani +12 more
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TLDR
It is suggested that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment.Abstract:
Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment.read more
Citations
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Spinal muscular atrophy
Stephen J. Kolb,John T. Kissel +1 more
TL;DR: There is an inverse correlation between SMN2 gene copy number and clinical severity, and clinical management focuses on multidisciplinary care.
Journal ArticleDOI
Spinal muscular atrophy: going beyond the motor neuron
TL;DR: Recent developments in understanding the function of SMN in cells above and beyond motor neurons are summarized, indicating that SMA may actually be a multi-system disorder.
Journal ArticleDOI
A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse
Paul Porensky,Chalermchai Mitrpant,Vicki L. McGovern,Adam K. Bevan,Kevin D. Foust,Brain K. Kaspar,Stephen D. Wilton,Arthur H.M. Burghes +7 more
TL;DR: It is suggested that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes, and the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.
Journal ArticleDOI
Spinal Muscular Atrophy: Diagnosis and Management in a New Therapeutic Era
TL;DR: An update is provided regarding the most common form of SMA, proximal or 5q‐SMA, and the contemporary approach to diagnosis and treatment and several promising therapeutics are now being tested in early‐phase clinical trials.
Journal ArticleDOI
Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy
TL;DR: It is suggested that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.
References
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Journal ArticleDOI
Identification and characterization of a spinal muscular atrophy-determining gene
Suzie Lefebvre,Lydie Burglen,Sophie Reboullet,Olivier Clermont,Philippe Burlet,Louis Viollet,Bernard Bénichou,Corinne Cruaud,Philippe Millasseau,Massimo Zeviani,Denis Le Paslier,Jean Frézal,Daniel Cohen,Jean Weissenbach,Arnold Munnich,Judith Melki +15 more
TL;DR: The inverted duplication of a 500 kb element in normal chromosomes is described and the critical region is narrowed to 140 kb within the telomeric region, suggesting that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.
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A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy
TL;DR: The failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer.
Journal ArticleDOI
Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse.
TL;DR: A transgenic mouse line is generated in which Cre-ER is ubiquitously expressed to permit temporally regulated Cre-mediated recombination in diverse tissues of the mouse at embryonic and adult stages and this inducible Cre system will be a broadly useful tool to modulate gene activity in mouse embryos, adults, and culture systems where temporal control is an important consideration.
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Reversal of Neurological Defects in a Mouse Model of Rett Syndrome
TL;DR: Using a mouse model, robust phenotypic reversal is demonstrated, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.
Journal ArticleDOI
Correlation between severity and SMN protein level in spinal muscular atrophy.
Suzie Lefebvre,Philippe Burlet,Qing Liu,Solange Bertrandy,Olivier Clermont,Arnold Munnich,Gideon Dreyfuss,Judith Melki +7 more
TL;DR: A marked deficiency of the SMN protein in SMA is shown and the molecular mechanism underlying the pathogenesis of the disease is elucidated by western blot and immunohistochemical analyses using antibodies raised against theSMN protein.