Clinical trial NCT01754441: Mechanisms of Cell Death in Spinal Muscular Atrophy
Official title: Mechanisms of Cell Death in Spinal Muscular Atrophy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
Motor Neuron Abnormalities
Lead sponsor: Nemours Children's Clinic
Sponsor class: OTHER
First posted: 2012-12-21
Enrollment: 25
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will enroll Children with Spinal Muscular Atrophy (SMA)

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.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of SMA confirmed by neurologist

Exclusion Criteria:

* Not seen as a patient at a participating Nemours facility

Primary outcomes:
measure: SMN localization in SMA fibroblasts
timeFrame: up to 2 years
Secondary outcomes:
measure: SMN isoform mRNA levels
timeFrame: up to 2 years
measure: Protein levels of putative SMA phenotypic modifiers
timeFrame: up to 2 years
measure: cell viability in response to DNA damaging agents
timeFrame: up to 2 years
measure: SMN protein levels
timeFrame: up to 2 years
measure: cell viability in response to cell death-inducing agents
timeFrame: up to 2 years
measure: SMN2 copy number
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Jacksonville
country: United States
facility: Nemours Children's Specialty Care, Jacksonville
state: Florida
Study officials:
affiliation: Nemours Biomedical Research
name: Matthew ER Butchbach, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.