SMN-Inducing Compounds For The Treatment Of Spinal Muscular Atrophy

Lorson, Monique A.; Lorson, Christian L.

doi:10.4155/fmc.12.131

Cited by 33 publications

(39 citation statements)

References 179 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pathological manifestation of SMA is motor neuron degeneration in the spinal cord, resulting in muscular atrophy and weakness [9]. Therefore, SMN promoting, muscle-enhancing and neuroprotective strategies have been considered as separate or complementary treatments of SMA [10,11].…”

Section: Introductionmentioning

confidence: 99%

Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

Tseng

Chen

Jong

et al. 2016

Pharmacological Research

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

Tseng

Chen

Jong

et al. 2016

Pharmacological Research

View full text Add to dashboard Cite

“…Modulating SMN2 expression to enhance the SMN protein and treat SMA is therefore a central therapeutic strategy (13,14). In SMA model mice, antisense oligonucleotides (ASOs) that correct the splicing defect of the SMN2 gene and restore SMN protein show remarkable benefit (15,16).…”

Section: Introductionmentioning

confidence: 99%

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

Kariya¹,

Obis²,

Garone³

et al. 2014

J. Clin. Invest.

128

104

View full text Add to dashboard Cite

Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs.

show abstract

“…As the copy number of the nearly identical SMN2 gene correlates with disease severity [21]–[23], SMA therapeutic development has primarily focused on enhancing the expression of full-length SMN from the SMN2 gene or through gene therapy [24]–[27]. To date, cell-based screens for SMA therapeutic discovery have employed reporter assays that monitor increased SMN2 transcription and exon 7 splicing [36]–[39].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, most efforts in developing SMA therapeutics have focused on methods to increase SMN protein levels. These include activation of the SMN2 promoter, enhancing inclusion of exon 7 in SMN2 -derived transcripts, increasing the stability of SMN mRNA and protein, or restoring SMN expression through gene therapy [24]–[27]. In agreement with the viability of these approaches, injection of AAV vectors encoding full-length SMN in mouse models of SMA resulted in remarkable correction of lifespan and motor function [28]–[31].…”

Section: Introductionmentioning

confidence: 98%

A Cell System for Phenotypic Screening of Modifiers of SMN2 Gene Expression and Function

Tisdale

Espinoza-Derout

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease caused by homozygous inactivation of the SMN1 gene and reduced levels of the survival motor neuron (SMN) protein. Since higher copy numbers of the nearly identical SMN2 gene reduce disease severity, to date most efforts to develop a therapy for SMA have focused on enhancing SMN expression. Identification of alternative therapeutic approaches has partly been hindered by limited knowledge of potential targets and the lack of cell-based screening assays that serve as readouts of SMN function. Here, we established a cell system in which proliferation of cultured mouse fibroblasts is dependent on functional SMN produced from the SMN2 gene. To do so, we introduced the entire human SMN2 gene into NIH3T3 cell lines in which regulated knockdown of endogenous mouse Smn severely decreases cell proliferation. We found that low SMN2 copy number has modest effects on the cell proliferation phenotype induced by Smn depletion, while high SMN2 copy number is strongly protective. Additionally, cell proliferation correlates with the level of SMN activity in small nuclear ribonucleoprotein assembly. Following miniaturization into a high-throughput format, our cell-based phenotypic assay accurately measures the beneficial effects of both pharmacological and genetic treatments leading to SMN upregulation. This cell model provides a novel platform for phenotypic screening of modifiers of SMN2 gene expression and function that act through multiple mechanisms, and a powerful new tool for studies of SMN biology and SMA therapeutic development.

show abstract

SMN-Inducing Compounds For The Treatment Of Spinal Muscular Atrophy

Cited by 33 publications

References 179 publications

Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

A Cell System for Phenotypic Screening of Modifiers of SMN2 Gene Expression and Function

Contact Info

Product

Resources

About