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Sponsors and Collaborators: |
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Nationwide Children's Hospital Muscular Dystrophy Association |
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Information provided by: | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) |
ClinicalTrials.gov Identifier: | NCT00494195 |
Limb girdle muscular dystrophy type 2D (LGMD2D) is a genetic disease that affects skeletal muscle. Insufficient levels of the protein alpha-sarcoglycan result in muscle weakness that worsens over time. The purpose of this study is to evaluate the safety and effectiveness of gene therapy in treating children and adults with LGMD2D.
Condition | Intervention | Phase |
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Muscular Dystrophies |
Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- Lower dose Genetic: Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- Higher dose |
Phase I |
Study Type: | Interventional |
Study Design: | Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Randomized, Safety/Efficacy Study, Treatment |
Official Title: | Phase I Gene Transfer of rAAV1.tMCK.Human-Alpha-Sarcoglycan for Limb Girdle Muscular Dystrophy Type 2D (LGMD2D) |
Estimated Enrollment: | 6 |
Study Start Date: | March 2008 |
Estimated Study Completion Date: | April 2012 |
Estimated Primary Completion Date: | January 2011 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
The first cohort will receive a total of 1.5 ml volume of study agent in two to six separate injections into the selected muscle (extensor digitorum brevis) or other muscle if more appropriate upon considering the individual patient. The dose will be 3.25 X 1011 vg in 1.5 ml. The anatomical midline point of the muscle will be identified on the skin and two to six vector injections will be distributed in the direction of an X. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.
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Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- Lower dose
The first cohort of subjects with LGMD2D (alpha-sarcoglycan deficiency) and proven mutations will undergo gene transfer in a standard three-six-dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. A minimum of three subjects will be enrolled into this cohort and will receive a total of 1.5 ml volume of study agent in two to six separate injections into the selected muscle (extensor digitorum brevis) or other muscle if more appropriate upon considering the individual patient. The dose will be 3.25 X 10 to the 11 vg in 1.5 ml. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo. |
2: Experimental
The second cohort will receive 6.5 X 10 to the 11 vg in 1.5 ml delivered to muscle according to the same paradigm. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.
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Genetic: Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- Higher dose
The second cohort will receive 6.5 X 10 to the 11 vg in 1.5 ml delivered to muscle according to the same paradigm. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.
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The primary objective of this study is the assessment of the safety of intramuscular administration to alpha-sarcoglycan deficient subjects of recombinant adeno-associated virus serotype 1 (rAAV1)-human alpha-sarcoglycan gene (hαSG) vector under control of a skeletal muscle creatine kinase promoter. The secondary objective is to determine the dose of rAAV1.tMCK.hαSG vector required to achieve a detectable level of alpha-sarcoglycan in muscle of subjects with this disorder.
A recombinant virus vector constructed from AAV1 has been altered to carry the human alpha-sarcoglycan gene expressed from a tMCK promoter. The construct has been shown to initiate the production of a functional alpha-sarcoglycan protein in laboratory animals. This construct can reverse the dystrophic phenotype in the alpha-sarcoglycan knock out mouse, a laboratory animal model for the clinical disorder. Intramuscular injection of rAAV1 restores muscle histology to normal and increases muscle strength to levels exceeding control knock out mice but not to the same degree as wild-type mice.
The proposed human clinical trial is a phase I, double-blind randomized protocol with injection of rAAV1.tMCK.hαSG gene vector into muscle. Two cohorts of subjects with LGMD2D (alpha-sarcoglycan deficiency), each with proven mutations, will undergo gene transfer in a standard three-six-dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. A minimum of three subjects will be enrolled into each cohort. The first cohort will receive a total of 1.5 ml volume of study agent in two to six separate injections into the selected muscle (extensor digitorum brevis) or other muscle if more appropriate (considering the individual patient) with a dose of 3.25 X 10 to the 11 vg in 1.5 ml. The anatomical midline point of the muscle will be identified on the skin and two to six vector injections will be distributed in the direction of an X. The second cohort will receive 6.5 X 10 to 11 vg in 1.5 ml delivered to muscle according to the same paradigm. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo. On the day of the vector infusion, 4 hours before gene transfer, patients will receive intravenous methylprednisolone 2.0 mg/kg (not to exceed 1 gm total), with repeat doses on two consecutive mornings. The methylprednisolone is specifically given to diminish the immediate inflammation from the needle injection, which is known to arouse an inflammatory reaction and could contribute to bringing antigen presenting cells to the site of vector delivery.
Safety endpoints to be assessed include inflammatory reaction to the vector, as evaluated by muscle biopsy, and changes in hematology, serum chemistry, urinalysis, immunologic responses to rAAV1 and alpha-sarcoglycan, and reported history and observations of symptoms. The patient will have 10 follow-up visits for the next 2 years after the initial infusion.
Ages Eligible for Study: | 5 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
United States, Ohio | |
The Research Institute at Nationwide Children's Hospital | Recruiting |
Columbus, Ohio, United States, 43205 | |
Contact: Xiomara Q. Rosales, MD 614-722-6961 rosalesx@ccri.net | |
Contact: Chris Shilling, MS 614-722-6961 chris.shilling@nationwidechildrens.org | |
Principal Investigator: Jerry R. Mendell, MD |
Principal Investigator: | Jerry R. Mendell, MD | The Research Institute at Nationwide Children's Hospital |
Responsible Party: | Nationwide Children's Hospital ( Jerry R. Mendell, M.D. Director of the Center for Gene Therapy ) |
Study ID Numbers: | 5U54 AR050733, 5U54AR050733, IRB07-00329 |
Study First Received: | June 27, 2007 |
Last Updated: | October 15, 2008 |
ClinicalTrials.gov Identifier: | NCT00494195 History of Changes |
Health Authority: | United States: Food and Drug Administration |
AAV AAV1 adeno-associated virus alpha-sarcoglycanopathy gene therapy gene transfer LGMD |
LGMD2D limb girdle limb girdle muscular dystrophy type 2D muscular dystrophy sarcoglycan SGCA |
Limb-girdle Muscular Dystrophy Virus Diseases Limb-girdle Muscular Dystrophy Type 2A Muscular Dystrophies Muscular Diseases Muscular Dystrophies, Limb-Girdle |
Genetic Diseases, Inborn Neuromuscular Diseases Musculoskeletal Diseases Muscular Disorders, Atrophic Atrophy Muscular Dystrophy |
Muscular Dystrophies Muscular Diseases Muscular Dystrophies, Limb-Girdle Genetic Diseases, Inborn |
Neuromuscular Diseases Musculoskeletal Diseases Muscular Disorders, Atrophic Nervous System Diseases |