An observational study in Spinal Muscular Atrophy, sponsored by Nemours Children's Clinic. Completed at 2 sites in United States. Open to participants aged Up to 21 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-02-21.
Sponsored by Nemours Children's Clinic · Observational
Spinal muscular atrophy is a genetically based disease that affects motor neurons in the spinal cord and leads to muscle wasting and weakness. The gene found to be responsible for the underlying disease is called the SMN or survival motor neuron gene. Individuals with SMA are either missing a copy of the gene or have a mutation in the gene. Although the gene has been identified, how it actually causes the motor neurons to die and leads to muscle wasting and weakness is not completely understood. The investigators have found that skin cells from children with SMA tend to be more susceptible to cell death when exposed to cell death inducing agents. In this protocol, The investigators wish to study the mechanisms by which these cells die when exposed to these agents and how this may be related to the gene defect and the disease.
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neurons and progressive muscle atrophy. The disease is one of the most common genetic causes of infant death. The gene responsible for SMA, survival motor neuron (SMN), exists in humans as two nearly identical copies (SMN1 and SMN2). Only deletion or mutation(s) of the telomeric copy of the gene (SMN1) causes the disease. The SMN protein has been known to function in assembly of the RNA splicing complex, however, the mechanism(s) by which SMN-deficiency causes cell death in SMA are not clear. The long-term goal is to understand the mechanism(s) of motor neuron death in SMA and develop a means of prevention. SMN protein has been reported to have some survival promoting functions in cultured cells. Preliminary studies show that skin fibroblasts from SMA patients are more sensitive to certain death promoting stimuli than control fibroblasts. The investigators hypothesize that the SMN protein is directly involved in cell survival and that loss of this survival function of SMA results in motor neuron death in SMA. The investigators will use fibroblasts from SMA patients, fibroblasts from controls without SMA, motor neuron-like cell lines (such as NSC-34) and rodent primary motor neuron cultures as model systems to test our hypothesis. The investigators will determine the effect of expression of SMN protein in regulating cell death of SMA fibroblasts. The investigators will further investigate the role of SMN in neuronal cell survival. Finally, the investigators will determine biological pathway(s) of SMN-mediated cell protection. Results from the proposed studies will provide insight into the mechanism(s) by which SMN protects cells from death and how a decrease in SMN function leads to the SMA phenotype. Ultimately, the obtained information could lead to develop therapeutic strategies for SMA.
494 studies on the registry are indexed under Muscular Atrophy; 94 are open to participants now.
This study's enrollment of 25 is below the median of 72 across 139 observational studies indexed under Muscular Atrophy.
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Of its 9 completed or terminated interventional studies of FDA-regulated products, 6 (67%) have results posted.
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This study will enroll Children with Spinal Muscular Atrophy (SMA)
Exclusion Criteria:
SMN localization in SMA fibroblasts
Established fibroblast lines from SMA patients will be immunolabeled with antibodies directed against SMN and examined for changes in the nuclear localization of SMN in gems.
Time frame: up to 2 years
SMN isoform mRNA levels
The levels of full-length SMN and SMNdelta7 (lacking exon 7) mRNA transcripts will be measured using quantitative PCR.
Time frame: up to 2 years
Protein levels of putative SMA phenotypic modifiers
The levels of previously identified modifiers of SMA clinical phenotype (i.e. plastin-3 and ZPR-1) will be examined by immunoblot.
Time frame: up to 2 years
cell viability in response to DNA damaging agents
The responsiveness of SMA fibroblasts to DNA damaging agents such as camptothecin, etoposide, bleomycin and actinomycin D will be measured using cell viability assays
Time frame: up to 2 years
SMN protein levels
SMN protein levels will be measured by immunoblot.
Time frame: up to 2 years
cell viability in response to cell death-inducing agents
The responsiveness of SMA fibroblasts to cell death-inducing agents such as staurosporine, tunicamycin and hydrogen peroxide will be examined using cell viability assays.
Time frame: up to 2 years
SMN2 copy number
SMN2 copy number will be determined by quantitative PCR of genomic DNA isolated from established fibroblast lines.
Time frame: up to 2 years
Plan to share: Undecided — De-identified data will be made available after publication.
This study is completed, as verified in Feb 2020. You cannot join it, but the record below documents what was studied.
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Nemours Children's Clinic