Clinical Trial: Gene Transfer Therapy for Treating Children and Adults With Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: Phase I Gene Transfer of rAAV1.tMCK.Human-alpha-sarcoglycan for Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)
Brief Summary: 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.
Detailed Summary:
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. 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 2 to 6 vector injections will be distributed in the direction of an X. The second co
Sponsor: Nationwide Children's Hospital
Current Primary Outcome: Safety of AAV1.tMCK.human-alpha-sarcoglycan gene transfer via intramuscular injection to the EDB muscle [ Time Frame: Measured throughout the study ]
Original Primary Outcome: Safety of AAV1.tMCK.human-alpha-sarcoglycan gene transfer via intramuscular injection to the tibialis anterior muscle [ Time Frame: throughout the study ]
Current Secondary Outcome:
- Human-alpha-sarcoglycan gene expression at the site of gene transfer via muscle biopsy [ Time Frame: First cohort: Measured 45 days for two patients and at 90 days after gene transfer for one patient; Second cohort: Measured at 6 months after gene transfer for the three patients ]
- Muscle strength of the gene transferred muscle via maximal volume isometric contraction testing (MVICT) if selected muscle is suitable for strenght testing [ Time Frame: Measured 45 or 90 days after gene transfer in the first cohort, or 6 months post-gene transfer in second cohort depending on muscle biopsy date ]
Original Secondary Outcome:
- Human-alpha-sarcoglycan gene expression at the site of gene transfer via muscle biopsy [ Time Frame: 90 days post-gene transfer ]
- Muscle strength of the gene transferred muscle via maximal volume isometric contraction testing (MVICT) [ Time Frame: 90 days post-gene transfer ]
Information By: Nationwide Children's Hospital
Dates:
Date Received: June 27, 2007
Date Started: March 2008
Date Completion:
Last Updated: February 4, 2013
Last Verified: February 2013
