Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

Nash, Leslie A.; Burns, Joseph K.; Warman‐Chardon, Jodi; Kothary, Rashmi; Parks, Robin J.

doi:10.2174/1566524016666161128113338

Cited by 85 publications

(87 citation statements)

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“…Accumulating evidence challenges the idea that SMA is solely a disease of motor neurons. SMA is increasingly described as a disease affecting tissues and cell types beyond the motor neuron, suggesting that effective disease intervention may require body‐wide correction of SMN protein levels to achieve a complete reversal or amelioration of the disease state . This is consistent with the requirement of peripheral SMN restoration for long‐term rescue in a severe SMA animal model …”

Section: Introductionsupporting

confidence: 61%

“…The hallmark of SMA is the progressive degeneration of α‐motor neurons in the brain stem and spinal cord that causes muscle atrophy, weakness, and disease‐related complications that can impact survival . Accumulating evidence challenges the idea that SMA is solely a disease of motor neurons.…”

Section: Introductionmentioning

confidence: 99%

“…SMN protein is ubiquitously expressed throughout the body and is implicated in several basic cellular functions . SMN protein may have a role in many cells and tissues, such as skeletal muscle, heart, bone, and autonomic and nervous systems; and deficiencies may contribute to the disease state …”

Section: Introductionmentioning

confidence: 99%

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Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Poirier

Weetall

Heinig

et al. 2018

Pharmacology Res & Perspec

137

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Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small‐molecule SMN2 pre‐mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose‐dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients’ blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Poirier

Weetall

Heinig

et al. 2018

Pharmacology Res & Perspec

137

View full text Add to dashboard Cite

show abstract

“…The exon 7-skipped transcript generated by SMN2 codes for SMNΔ 7, a partially functional and unstable protein [15–17]. Loss of SMN1 creates SMN deficit, leading to spinal muscular atrophy (SMA), a major genetic disease of children and infants [18, 19]. Aberrant expression and/or localization of SMN have been associated with several other diseases, including amyotrophic lateral sclerosis (ALS), metabolic disorders, male infertility, and stress-associated disorders [14, 20–22].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

113

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Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

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“…Due the pronounced effects of motor neuron degeneration in patients, much of the research on SMN deficiency has focused on these cells in SMA. However, with the development of numerous mouse models of SMA, there is growing evidence that other cell types and tissues are affected by the disease (reviewed in Shababi et al 2014; Nash et al 2016). While both males and females are affected by SMA, there is evidence supporting the existence of sex-specific manifestations of the disease that have not been extensively explored.…”

Section: Introductionmentioning

confidence: 99%

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

2017

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Low levels of the survival of motor neuron (SMN) protein cause the neurodegenerative disease spinal muscular atrophy (SMA). SMA is a pediatric disease characterized by spinal motor neuron degeneration. SMA exhibits several levels of severity ranging from early antenatal fatality, to only mild muscular weakness and disease prognosis is related directly to the amount of functional SMN protein that a patient is able to express. Current therapies are being developed to increase the production of functional SMN protein, however understanding the effect that natural stresses have on the production and function of SMN is of critical importance to ensuring that these therapies will have the greatest possible effect for patients. Research has shown that SMN, both on the mRNA and protein level, is highly affected by cellular stress. In this review we will summarize the research that highlights the roles of SMN in the disease process and the response of SMN to various environmental stresses.

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Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

Cited by 85 publications

References 0 publications

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

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