The study will evaluate the tolerability, safety and efficacy of gene therapy product in boys with Duchenne muscular dystrophy (DMD). In Phase I the participants will be included in two sequential dose cohorts with increasing doses of the investigational product. Based on the results of Phase I, the dose of the investigational product for use in Phase II will be determined. Phase II is a randomized, single-blind, placebo-controlled study. The participants who are randomized to the placebo arm will have an opportunity for treatment with gene therapy at the beginning of the second year.
Written informed consent for participation in the trial.
Ambulatory boys aged 4-9 years with a documented diagnosis of DMD and clinical manifestations of the disease.
A frameshift mutation or nonsense mutation in the DMD gene.
Сreatine phosphokinase level >5000 U/L.
Hypersensitivity to any component of GNR-097 or placebo.
Patient with cognitive impairment or a sedentary lifestyle that, in the opinion of the investigator, may interfere with the development or manifestation of motor activity.
Mutations in exons 8 and/or 9 of the DMD gene; for patients planned for inclusion in Cohort A, additionally: mutations in exons 1-17 and/or 59-71 of the DMD gene.
Clinical signs of cardiomyopathy, including left ventricular ejection fraction (Simpson) <40% based on echocardiography performed during screening.
Parallel
GNR-097
GeneticSingle IV infusion of GNR-097 (recombinant adeno-associated virus, serotype 9 (AAV9) carrying a truncated human dystrophin gene (micro-dystrophin)).
Placebo followed by GNR-097
GeneticSingle IV infusion of matching placebo followed by single IV infusion of GNR-097 at the beginning of the second year.
Number and percentage of participants with treatment-emergent adverse events (AEs), AEs of special interest and serious adverse events (SAEs)
AEs of special interest include immune-mediated myositis, myocarditis, thrombotic microangiopathy and hemolytic uremic syndrome
Antibodies to AAV9 and microdystrophin
Presence and titer of binding and neutralizing antibodies to AAV9 and total antibodies to microdystrophin as measured by ELISA
Quantity of dystrophin and microdystrophin in biopsied muscle
Measured by Western blot
Percentage of dystrophin-positive muscle fibers in biopsied muscle
Measured by immunohistochemistry (IHC)
Intensity of immunofluorescence of muscle fibers in biopsied muscle when they are stained for dystrophin
Measured by IHC
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