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NCT Number: NCT01754441

Mechanisms of Cell Death in Spinal Muscular Atrophy

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.

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Key information

Conditions

Spinal Muscular Atrophy Central Nervous System Diseases Motor Neuron Disease Muscular Atrophy, Spinal Nervous System Diseases Neurodegenerative Diseases Neuromuscular Diseases Spinal Cord Diseases

Age range

Up to 21 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Diagnosis of SMA confirmed by neurologist

Exclusion criteria

  • Not seen as a patient at a participating Nemours facility

Treatment and study plan

Primary outcomes

  1. SMN localization in SMA fibroblasts

    Time frame: up to 2 years

    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.

Secondary outcomes

  1. SMN isoform mRNA levels

    Time frame: up to 2 years

    The levels of full-length SMN and SMNdelta7 (lacking exon 7) mRNA transcripts will be measured using quantitative PCR.

  2. Protein levels of putative SMA phenotypic modifiers

    Time frame: up to 2 years

    The levels of previously identified modifiers of SMA clinical phenotype (i.e. plastin-3 and ZPR-1) will be examined by immunoblot.

  3. cell viability in response to DNA damaging agents

    Time frame: up to 2 years

    The responsiveness of SMA fibroblasts to DNA damaging agents such as camptothecin, etoposide, bleomycin and actinomycin D will be measured using cell viability assays

  4. SMN protein levels

    Time frame: up to 2 years

    SMN protein levels will be measured by immunoblot.

  5. cell viability in response to cell death-inducing agents

    Time frame: up to 2 years

    The responsiveness of SMA fibroblasts to cell death-inducing agents such as staurosporine, tunicamycin and hydrogen peroxide will be examined using cell viability assays.

  6. SMN2 copy number

    Time frame: up to 2 years

    SMN2 copy number will be determined by quantitative PCR of genomic DNA isolated from established fibroblast lines.

Sponsors and collaborators

Lead sponsor

Nemours Children's Clinic

Other

Registry information

Important dates

Study start
2008
Primary completion
2020
Study completion
2020
First posted
Dec 21, 2012
Registry last updated
Feb 21, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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