Muscular Dystrophies Clinical Trial
Official title:
Phase I Gene Transfer of rAAV1.tMCK.Human-alpha-sarcoglycan for Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)
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.
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 cohort will receive the same dose 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. We
have previously demonstrated that this treatment enhances gene expression by at least 2-fold
(Included as part of BB-IND-12936 for minidystrophin gene transfer).
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 to 12 follow-up visits for the next 2 years after the initial infusion.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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