Mechanisms of Cell Death in Spinal Muscular Atrophy

Status:Enrolling by invitation
Conditions:Neurology, Neurology, Orthopedic
Therapuetic Areas:Neurology, Orthopedics / Podiatry
Age Range:Any - 21
Start Date:May 2008
End Date:December 2017

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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.

Inclusion Criteria:

- Diagnosis of SMA confirmed by neurologist

Exclusion Criteria:

- Not seen as a patient at a participating Nemours facility
We found this trial at
1600 Rockland Road
Wilmington, Delaware 19803
(302) 651-4200
Alfred I. duPont Hospital for Children Nemours began more than 70 years ago with the...
Wilmington, DE
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Jacksonville, FL
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13535 Nemours Parkway
Orlando, Florida 32827
(407) 567-4000
Nemours Children's Hospital Nemours Children's Hospital in Orlando brings pediatric specialty care never before offered...
Orlando, FL
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