The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients that will involve direct intramuscular injection to the extensor digitorum brevis muscle (EDB).
This is a phase I safety and tolerability study. Three DMD subjects will receive bilateral injections into the EDB muscle, with one EDB receiving the GALGT2 vector (rAAVrh74.MCK.GALGT2) and the other side receiving saline alone (assigned in a randomized fashion). Three subjects will receive a single gene transfer dose of 1E12 vector genomes, and patients and investigators will be blinded as to which muscle is injected with vector. Muscle biopsies will be performed at three months (12 weeks) in two subjects and at 1.5 months (6 weeks) in one subject and evaluated blindly for the expression of the GALGT2 transgene.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Direct intramuscular injection of rAAVrh74.MCK.GALGT2 transferred to the extensor digitorum brevis muscle (EDB) of one foot and the other side receiving saline alone.
Direct intramuscular injection of rAAVrh74.MCK.GALGT2 transferred to the extensor digitorum brevis muscle (EDB) of one foot and the OTHER side receiving saline alone.
Nationwide Children's Hospital
Columbus, Ohio, United States
Treatment related toxicities
Based on the development of unacceptable toxicity defined as the occurrence of any one Grade III or higher treatment-related toxicities.
Time frame: 2 years
Expression of GALGT2 demonstrated with anti-CT epitope antibodies.
Time frame: 6 or 12 weeks
GALGT2 protein expression quantified by western blot and assessed by densitometry
Time frame: 6 or 12 weeks
Transduction efficiency measured by qPCR of the GALGT transgene from muscle, and expressed as vector genomes normalized to a genomic single-copy control.
Time frame: 6 or 12 weeks
Number of fibers containing central nuclei compared between muscles by paired t-tests
Time frame: 6 or 12 weeks
Dystrophin expression demonstrated with antibodies to N-terminal, C-terminal, and rod domains
Time frame: 6 or 12 weeks
Utrophin expression
Time frame: 6 or 12 weeks
Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387
Time frame: 6 or 12 weeks
Muscle will be examined for histological appearance
Time frame: 6 or 12 weeks
Antibodies to rAAVrh74 along with PBMC ELISpots to both rAAVrh74 capsid and GALGT protein will be evaluated at different time points during the study
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Time frame: 6 or 12 weeks