Clinical Study of Spinal Muscular Atrophy
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Neurology, Orthopedic |
| Therapuetic Areas: | Neurology, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 2/8/2017 |
| Start Date: | May 2005 |
| End Date: | December 2022 |
Spinal Muscular Atrophy (SMA) is the leading genetic cause of death in infancy. It is a
devastating disease that leads to progressive loss of those nerve cells that control our
muscle bulk and movement. Patients develop increasing weakness in all muscles, eventually
including those needed for breathing. In more than half of patients, SMA starts in infancy
and typically leads to death within the first 2 years of life. In others, the disease begins
in childhood and leads to significant disability.
SMA is caused by a defect in the "Survival of Motor Neurons" (SMN1) gene. Researchers are
hopeful to find a cure, because nature has provided humans with a second gene, almost an
identical copy of the SMN1 gene. Normally, the second gene does not contribute much, but
researchers think that its function can be increased by medications.
To find out whether these medications help patients with SMA, we have to conduct clinical
trials. Here, we propose to prepare for clinical trials. We will invite SMA patients to join
our research effort. We will examine them regularly to better understand their disease. The
visits will include questions, physical exam, blood drawing, and sometimes X-rays and a skin
biopsy. We will use modern computer methods to process the information. While we are doing
this, we will plan a clinical trial. Once the clinical trial begins, we will offer SMA
patients participation if they meet the criteria for that trial.
We will make sure that the participants' privacy is maintained and that the study risks are
as low as possible.
Identifying an effective SMA treatment is very important because there is currently none.
Clinical trials are the only way to decide whether a new treatment works in SMA patients or
not.
devastating disease that leads to progressive loss of those nerve cells that control our
muscle bulk and movement. Patients develop increasing weakness in all muscles, eventually
including those needed for breathing. In more than half of patients, SMA starts in infancy
and typically leads to death within the first 2 years of life. In others, the disease begins
in childhood and leads to significant disability.
SMA is caused by a defect in the "Survival of Motor Neurons" (SMN1) gene. Researchers are
hopeful to find a cure, because nature has provided humans with a second gene, almost an
identical copy of the SMN1 gene. Normally, the second gene does not contribute much, but
researchers think that its function can be increased by medications.
To find out whether these medications help patients with SMA, we have to conduct clinical
trials. Here, we propose to prepare for clinical trials. We will invite SMA patients to join
our research effort. We will examine them regularly to better understand their disease. The
visits will include questions, physical exam, blood drawing, and sometimes X-rays and a skin
biopsy. We will use modern computer methods to process the information. While we are doing
this, we will plan a clinical trial. Once the clinical trial begins, we will offer SMA
patients participation if they meet the criteria for that trial.
We will make sure that the participants' privacy is maintained and that the study risks are
as low as possible.
Identifying an effective SMA treatment is very important because there is currently none.
Clinical trials are the only way to decide whether a new treatment works in SMA patients or
not.
Spinal Muscular Atrophy (SMA) is one of the most devastating neurological diseases of
childhood. Affected infants and children suffer from progressive muscle weakness caused by
degeneration of lower motor neurons in the spinal cord and brainstem. Clinically, four
phenotypes are distinguished within the continuous spectrum of disease severity based on the
age of onset and the highest motor milestone ever achieved. SMA is caused by homozygous
deletion of the survival motor neuron-1 (SMN1) gene. A related gene, SMN2, produces low
levels of full-length SMN protein due to inefficient splicing. There is an inverse
correlation between SMN copy number and disease severity, presumably mediated by levels of
full length SMN protein. Therefore, increasing the amount of full-length SMN protein is a
promising treatment strategy. Several drugs targeting splicing efficiency have resulted in
increased SMN protein in preclinical assays and are now awaiting clinical testing.
With the future objective to conduct clinical trials in SMA, the proposed project has 3
specific aims: 1) To establish a web-based database that will serve to enroll the patient
population and that will facilitate timely recruitment for future clinical trials; (2) to
plan for clinical trials by a) developing reliable outcome measures, and (b) establishing
the infrastructure needed to carry out efficient clinical trials, (c) convening meetings of
preclinical and clinical researchers involved in SMA drug development to select candidate
drugs, and (3) to characterize the patient population from a clinical and molecular point of
view.
We have established a Pediatric Neuromuscular Clinical Research Network (PNCR) to evaluate
patients at three sites: New York, Boston and Philadelphia. Data management (including fully
web-based data repository) and statistical analyses will be carried out at the University of
Rochester by the "Muscle Study Group Data Center", which is a group experienced in clinical
trials of neuromuscular disease. We will characterize the patient population using selected
outcome measures, standardized among sites. The clinical trial planning phase will focus on
developing the necessary infrastructure between sites, critically evaluating candidate
outcome measures, obtaining pilot data using those outcome measures, and establishing their
reliability. In parallel to the proposed study we will work closely with the preclinical
units of the Columbia University SMA research center to identify and prioritize candidate
drugs for future clinical trials. Finally, based on the observational data from the proposed
study, and discussions among the network's clinical experts we will develop efficient phase
I/II clinical trial designs to test candidate drugs. This clinical research is timely and
relevant, because laboratory research has identified candidate drugs for SMA. There is
currently no effective treatment for this devastating disease. All activities of the Network
will conform to established regulations that govern clinical research and patient privacy
(HIPAA).
childhood. Affected infants and children suffer from progressive muscle weakness caused by
degeneration of lower motor neurons in the spinal cord and brainstem. Clinically, four
phenotypes are distinguished within the continuous spectrum of disease severity based on the
age of onset and the highest motor milestone ever achieved. SMA is caused by homozygous
deletion of the survival motor neuron-1 (SMN1) gene. A related gene, SMN2, produces low
levels of full-length SMN protein due to inefficient splicing. There is an inverse
correlation between SMN copy number and disease severity, presumably mediated by levels of
full length SMN protein. Therefore, increasing the amount of full-length SMN protein is a
promising treatment strategy. Several drugs targeting splicing efficiency have resulted in
increased SMN protein in preclinical assays and are now awaiting clinical testing.
With the future objective to conduct clinical trials in SMA, the proposed project has 3
specific aims: 1) To establish a web-based database that will serve to enroll the patient
population and that will facilitate timely recruitment for future clinical trials; (2) to
plan for clinical trials by a) developing reliable outcome measures, and (b) establishing
the infrastructure needed to carry out efficient clinical trials, (c) convening meetings of
preclinical and clinical researchers involved in SMA drug development to select candidate
drugs, and (3) to characterize the patient population from a clinical and molecular point of
view.
We have established a Pediatric Neuromuscular Clinical Research Network (PNCR) to evaluate
patients at three sites: New York, Boston and Philadelphia. Data management (including fully
web-based data repository) and statistical analyses will be carried out at the University of
Rochester by the "Muscle Study Group Data Center", which is a group experienced in clinical
trials of neuromuscular disease. We will characterize the patient population using selected
outcome measures, standardized among sites. The clinical trial planning phase will focus on
developing the necessary infrastructure between sites, critically evaluating candidate
outcome measures, obtaining pilot data using those outcome measures, and establishing their
reliability. In parallel to the proposed study we will work closely with the preclinical
units of the Columbia University SMA research center to identify and prioritize candidate
drugs for future clinical trials. Finally, based on the observational data from the proposed
study, and discussions among the network's clinical experts we will develop efficient phase
I/II clinical trial designs to test candidate drugs. This clinical research is timely and
relevant, because laboratory research has identified candidate drugs for SMA. There is
currently no effective treatment for this devastating disease. All activities of the Network
will conform to established regulations that govern clinical research and patient privacy
(HIPAA).
Inclusion Criteria
- Clinical diagnosis of Spinal Muscular Atrophy
- Genetic diagnosis of SMN gene deletion
- Parents or if applicable subjects must give informed consent
- must be capable of complying with the study procedures
- Female subjects of child-bearing potential must agree to undergo pregnancy test prior
to radiological studies
- Diagnosis of SMA before age 19 years
Exclusion Criteria:
- Unstable medical condition precluding participation
- Significant respiratory compromise that would interfere with safe travel to site of
evaluation. (The clinical site PI decides when air travel is not recommended and when
the patient's location is not within a reasonably safe driving distance (upper limit
150-250 miles)
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