Follistatin Gene Transfer to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, Infectious Disease, Neurology, Orthopedic |
| Therapuetic Areas: | Immunology / Infectious Diseases, Neurology, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 11/25/2017 |
| Start Date: | January 2012 |
| End Date: | October 2017 |
Phase I Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis.
The investigators are performing a gene therapy clinical trial in Becker muscular dystrophy
(BMD) and sporadic inclusion body myositis (sIBM) patients. Both of these conditions have an
important common feature: loss of ability to walk because of weakness of the thigh muscles.
The investigators plan to do a gene therapy trial to deliver a gene to muscle called
follistatin (FS344) that can build muscle size and strength. If successful, the investigators
can increase the size of the thigh muscle and potentially prolong a patient's ability to
walk. The gene will be carried into the muscle by a virus called adeno-associated virus
(AAV). This virus occurs naturally in muscle and does not cause any human disease, setting
the stage for its safe use in a clinical trial.
Presently there is no treatment that can reverse Becker muscular dystrophy or sporadic
inclusion body myositis. Only supportive care is currently possible.
In this study, subjects with either of these diseases will have shots of the follistatin gene
injected directly into thigh muscle on one (first cohort) or both legs (2nd and 3rd cohort).
One hundred and eighty days following the gene delivery, the muscle will undergo biopsy to
look closely at the muscle to see if the muscle fibers are bigger. Between the time of the
gene transfer and the muscle biopsy, patients will be carefully monitored for any side
effects of the treatment. This will include an MRI of the thigh muscle before treatment and
at day 180 following treatment. Blood and urine tests, as well as physical examination will
be done on the subjects during the screening visit and on days 0, 1, 2, 7, 14, 30, 60, 90,
and 180 to make sure that there are no side effects from the gene injections. Sutures will be
removed 2 weeks post-biopsy.
Additional blood samples will be collected at 9, 12, 18, and 24 months. Patients will be seen
at the end of 1st and 2nd years for a physical exam, assessment of muscle strength and
appropriate blood tests.
(BMD) and sporadic inclusion body myositis (sIBM) patients. Both of these conditions have an
important common feature: loss of ability to walk because of weakness of the thigh muscles.
The investigators plan to do a gene therapy trial to deliver a gene to muscle called
follistatin (FS344) that can build muscle size and strength. If successful, the investigators
can increase the size of the thigh muscle and potentially prolong a patient's ability to
walk. The gene will be carried into the muscle by a virus called adeno-associated virus
(AAV). This virus occurs naturally in muscle and does not cause any human disease, setting
the stage for its safe use in a clinical trial.
Presently there is no treatment that can reverse Becker muscular dystrophy or sporadic
inclusion body myositis. Only supportive care is currently possible.
In this study, subjects with either of these diseases will have shots of the follistatin gene
injected directly into thigh muscle on one (first cohort) or both legs (2nd and 3rd cohort).
One hundred and eighty days following the gene delivery, the muscle will undergo biopsy to
look closely at the muscle to see if the muscle fibers are bigger. Between the time of the
gene transfer and the muscle biopsy, patients will be carefully monitored for any side
effects of the treatment. This will include an MRI of the thigh muscle before treatment and
at day 180 following treatment. Blood and urine tests, as well as physical examination will
be done on the subjects during the screening visit and on days 0, 1, 2, 7, 14, 30, 60, 90,
and 180 to make sure that there are no side effects from the gene injections. Sutures will be
removed 2 weeks post-biopsy.
Additional blood samples will be collected at 9, 12, 18, and 24 months. Patients will be seen
at the end of 1st and 2nd years for a physical exam, assessment of muscle strength and
appropriate blood tests.
Inclusion Criteria:
- All subjects [sIBM and BMD must be ambulatory and have identifiable atrophy of the
quadriceps muscle with muscle weakness ≥2 standard deviations below predicted using
quantitative muscle testing (maximum voluntary isometric strength testing), and
difficulty getting out of chairs, climbing stairs, and getting up from the floor.
- sIBM patients include males and post-menopause females of any ethnic or racial group.
Diagnosis of sIBM is based on previously published criteria that include distribution
of weakness (knee extensor weakness, finger flexor weakness) and histological presence
of inflammation and vacuolar myopathy. Patients with inflammation, vacuolar changes
and intracellular amyloid deposits or 15/18nm filaments fulfill criteria irrespective
of clinical features.
- BMD patients include adult males (>18yo) of any ethnic or racial group with proven
mutation of dystrophin gene and continued ambulation after age 15 years old.
- Ability to cooperate for muscle testing
- Deficit in muscle strength greater than 2 standard deviation below age expectations
- Willingness of sexually active subjects with reproductive capacity (only male
population) to practice reliable method of contraception until two negative sperm
samples are obtained post gene transfer
Exclusion Criteria:
- Active viral infection
- History or evidence of active infection with hepatitis C, hepatitis A or B, or HIV
- Patients with any other cause of muscle weakness based on medical history and
screening physical exam including: myopathy (other dystrophies, polymyositis, and
dermatomyositis), neuropathy (from any cause), myasthenia gravis, and weakness related
to degenerative joint disease of the spine.
- Ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of
starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate,
cyclophosphamide, intravenous immunoglobulin, rituximab)
- Concomitant illness or requirement for chronic drug treatment that in the opinion of
the PI creates unnecessary risks for gene transfer. Patients taking any of the
following drugs will be excluded: drugs for treatment of myopathy or neuropathy or
agents used to treat diabetes mellitus
- Knee or ankle contractures preventing proper muscle strength testing
- Patients with AAV1 neutralizing antibody titers ≥ 1:1600 as determined by ELISA
immunoassay
- Patients with history of angina and patients with past history of myocardial
infarction in the past 6 months
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