Spinal Muscular AtrophyNCT01754441
Mechanisms of Cell Death in Spinal Muscular Atrophy
An observational study of Spinal Muscular Atrophy, run by Nemours Children's Clinic at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 21 yearsHealthy volunteers can take part
- Conditions the study is for
- Spinal Muscular Atrophy
- How many people
- 25 participants
- Where
- 2 sitesUnited States
- Study dates
- May 2008to Feb 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 21 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: This study will enroll Children with Spinal Muscular Atrophy (SMA)
Who may be able to join
- Diagnosis of SMA confirmed by neurologist
Who cannot join
- Not seen as a patient at a participating Nemours facility
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Nemours Children's Specialty Care, Jacksonville
Jacksonville, Florida, 32207
Alfred I. duPont Hospital for Children
Wilmington, Delaware, 19803
About this study
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.
Read the 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
- Keywords
- Spinal Muscular Atrophy, SMA, Motor Neuron Abnormalities
- Medical subject headings
- Muscular Atrophy, Spinal
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: up to 2 years
Secondary outcomes (6)
SMN isoform mRNA levels
The levels of full-length SMN and SMNdelta7 (lacking exon 7) mRNA transcripts will be measured using quantitative PCR.
Measured: 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.
Measured: 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
Measured: up to 2 years
SMN protein levels
SMN protein levels will be measured by immunoblot.
Measured: 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.
Measured: up to 2 years
SMN2 copy number
SMN2 copy number will be determined by quantitative PCR of genomic DNA isolated from established fibroblast lines.
Measured: up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2012 (estimated)
- Study startMay 2008
- Primary completionFeb 2020
- Study completionFeb 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Spinal Muscular AtrophyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nemours Children's Clinic
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Matthew E. R. Butchbach, Ph.D., Nemours Children's Clinic
- Investigators
- Matthew ER Butchbach, Ph.D., Principal investigator, Nemours Biomedical Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01754441
- Sponsor's protocol ID
- 82008
- Status last verified
- Feb 2020
- First submitted
- 13 Dec 2012
- Last updated
- 21 Feb 2020
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided: De-identified data will be made available after publication.
Publications
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.
PubMed 26247043Stabley 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.
PubMed 28284873
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms of Cell Death in Spinal Muscular Atrophy
- ClinicalTrials.gov ID
- NCT01754441
- Acronym / sponsor ID
- 82008
- Conditions
- Spinal Muscular Atrophy
- Keywords
- Spinal Muscular Atrophy, SMA, Motor Neuron Abnormalities
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Nemours Children's ClinicUniversity, hospital or other
- Study start
- May 2008
- Primary completion
- Feb 2020 (actual)
- Study completion
- Feb 2020 (actual)
- First posted
- 21 Dec 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Other
- Time perspective
- Prospective
Who may qualify
- Ages
- Up to 21 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- This study will enroll Children with Spinal Muscular Atrophy (SMA)
Key inclusion criteria (1 listed)
- Diagnosis of SMA confirmed by neurologist
Key exclusion criteria (1 listed)
- Not seen as a patient at a participating Nemours facility
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
6 secondary outcomes
SMN isoform mRNA levels
Time frame: up to 2 years
Protein levels of putative SMA phenotypic modifiers
Time frame: up to 2 years
cell viability in response to DNA damaging agents
Time frame: up to 2 years
SMN protein levels
Time frame: up to 2 years
cell viability in response to cell death-inducing agents
Time frame: up to 2 years
SMN2 copy number
Time frame: up to 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2020.
- Results publication: PubMed 26247043Stabley 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.
- Results publication: PubMed 28284873Stabley 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.
- Individual participant dataSharing planned: Undecided. De-identified data will be made available after publication.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Matthew ER Butchbach, Ph.D. principal investigator
Nemours Biomedical Research
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Spinal Muscular Atrophy, run by Nemours Children's Clinic at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
SMN localization in SMA fibroblasts (time frame: up to 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01754441, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2020.