Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

Butchbach, Matthew E.R.; Edwards, Jonathan; Burghes, Arthur H.M.

doi:10.1016/j.nbd.2007.04.009

Cited by 99 publications

(138 citation statements)

References 60 publications

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“…In severe SMA mouse models, the ability of SMA mice to turn over when placed on their backs and the time at which they turn is a sensitive measurement of the phenotype and an assessment of gross motor ability (27). Time-to-right assays were performed on mice in the following groups: SMA untreated; SMA treated with MO E1v11 alone; or SMA treated with MO E1v11 plus AAV9-PLS3.…”

Section: E1v11mentioning

confidence: 99%

Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

Kaifer¹,

Villalón²,

Osman³

et al. 2017

JCI Insight

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Section: E1v11mentioning

confidence: 99%

Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

Kaifer¹,

Villalón²,

Osman³

et al. 2017

JCI Insight

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“…Mice were subjected to periodic behavioral testing using assays that had previously been validated for this animal model (35,36). Treated SMA mice at 16 days were healthier than their untreated age-matched counterparts, who looked emaciated and were often paralyzed ( Figure 5A).…”

Section: Figurementioning

confidence: 99%

CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy

Passini¹,

Bu²,

Roskelley³

et al. 2010

J. Clin. Invest.

268

239

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Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of survival motor neuron (SMN) due to mutations in the SMN1 gene. In this study, an adeno-associated virus (AAV) vector expressing human SMN (AAV8-hSMN) was injected at birth into the CNS of mice modeling SMA. Western blot analysis showed that these injections resulted in widespread expression of SMN throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including increased myofiber size and improved neuromuscular junction architecture. Treated mice also displayed substantial improvements on behavioral tests of muscle strength, coordination, and locomotion, indicating that the neuromuscular junction was functional. Treatment with AAV8-hSMN increased the median life span of mice with SMA-like disease to 50 days compared with 15 days for untreated controls. Moreover, injecting mice with SMA-like disease with a human SMN-expressing self-complementary AAV vector -a vector that leads to earlier onset of gene expression compared with standard AAV vectors -led to improved efficacy of gene therapy, including a substantial extension in median survival to 157 days. These data indicate that CNS-directed, AAV-mediated SMN augmentation is highly efficacious in addressing both neuronal and muscular pathologies in a severe mouse model of SMA.

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“…Mice were weighed daily from birth and weekly thereafter. Righting reflex was used to evaluate muscle strength as previously described (56). Briefly, pups were turned over onto their backs, and latency to stably place all 4 paws on the bench top was recorded.…”

Section: Phenotypic Assessment Of Micementioning

confidence: 99%

Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

Lutz¹,

Kariya²,

Patruni³

et al. 2011

J. Clin. Invest.

153

127

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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.

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Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

Cited by 99 publications

References 60 publications

Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy

Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

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