Mechanisms of Cell Death in Spinal Muscular Atrophy

NCT ID: NCT01754441

Last Updated: 2020-02-21

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 25 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2008-05-31
• Study Completion Date: 2020-02-29

Brief Summary

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.

Detailed Description

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.

Conditions

Spinal Muscular Atrophy

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: PROSPECTIVE

Eligibility Criteria

Inclusion Criteria

• Diagnosis of SMA confirmed by neurologist

Exclusion Criteria

• Not seen as a patient at a participating Nemours facility

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Nemours Children's Clinic

OTHER

Sponsor Role: lead

Responsible Party

Matthew E. R. Butchbach, Ph.D.

Research Scientist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Matthew ER Butchbach, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Nemours Biomedical Research

Locations

Alfred I. duPont Hospital for Children

Wilmington, Delaware, United States

Nemours Children's Specialty Care, Jacksonville

Jacksonville, Florida, United States

Countries

United States

References

Stabley DL, Harris AW, Holbrook J, Chubbs NJ, Lozo KW, Crawford TO, Swoboda KJ, Funanage VL, Wang W, Mackenzie W, Scavina M, Sol-Church K, Butchbach ME. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR. Mol Genet Genomic Med. 2015 Jul;3(4):248-57. doi: 10.1002/mgg3.141. Epub 2015 Mar 21.

Reference Type: RESULT

PMID: 26247043 (View on PubMed)

Stabley DL, Holbrook J, Harris AW, Swoboda KJ, Crawford TO, Sol-Church K, Butchbach MER. Establishing a reference dataset for the authentication of spinal muscular atrophy cell lines using STR profiling and digital PCR. Neuromuscul Disord. 2017 May;27(5):439-446. doi: 10.1016/j.nmd.2017.02.002. Epub 2017 Feb 6.

Reference Type: RESULT

PMID: 28284873 (View on PubMed)

Other Identifiers

82008

Identifier Type: -

Identifier Source: org_study_id