Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Phase I Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Biological: rAAVrh74.MCK.GALGT2
* Other: PLACEBO (Saline)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nonambulant subjects, age 9 or older Confirmed mutation in the DMD gene using a clinically accepted technique that completely defines the mutation A magnetic resonance image of the EDB showing preservation of sufficient muscle mass to permit transfection Males of any ethnic group will be eligible Ability to cooperate with all study procedures Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate). Stable dose of corticosteroid therapy (including either prednisone or deflazacort and their generic forms) for 12 weeks prior to gene transfer Exclusion Criteria: Active viral infection based on clinical observations. The presence of a DMD mutation without weakness or loss of function Symptoms or signs of cardiomyopathy, including: Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs Echocardiogram with ejection fraction below 40% Serological evidence of HIV infection, or Hepatitis A, B or C infection Diagnosis of (or ongoing treatment for) an autoimmune disease Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer Subjects with rAAVrh74 binding antibody titers ≥ 1:400 as determined by ELISA immunoassay Presence of circulating anti-Sda antibodies as determined by study approved laboratory. Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory

Ages Eligible for Study
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Minimum Age: 9 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GALGT2 Viral Vector<br>Dose: 1E12 vg (total dose) (n=3) of rAAVrh74.MCK.GALGT2 vs Placebo (Saline). All participants will receive rAAVrh74.MCK.GALGT2 in the right or the left EDB muscle and receive Saline in the opposite EDB muscles. The investigator will not know which side will receive rAAVrh74.MCK.GALGT2 vs Saline until after the trial is over. At the end of the trial the investigator will be unblinded. | Biological: rAAVrh74.MCK.GALGT2<br>* 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.<br>|
| Experimental: Saline<br>Dose: 1E12 vg (total dose) (n=3) of rAAVrh74.MCK.GALGT2 vs Placebo (Saline). All participants will receive rAAVrh74.MCK.GALGT2 in the right or the left EDB muscle and receive Saline in the opposite EDB muscles. The investigator will not know which side will receive rAAVrh74.MCK.GALGT2 vs Saline until after the trial is over. At the end of the trial the investigator will be unblinded. | Other: PLACEBO (Saline)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related toxicities | Based on the development of unacceptable toxicity defined as the occurrence of any one Grade III or higher treatment-related toxicities. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of GALGT2 demonstrated with anti-CT epitope antibodies. |  | 6 or 12 weeks | 
| GALGT2 protein expression quantified by western blot and assessed by densitometry |  | 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. |  | 6 or 12 weeks | 
| Number of fibers containing central nuclei compared between muscles by paired t-tests |  | 6 or 12 weeks | 
| Dystrophin expression demonstrated with antibodies to N-terminal, C-terminal, and rod domains |  | 6 or 12 weeks | 
| Utrophin expression |  | 6 or 12 weeks | 
| Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387 |  | 6 or 12 weeks | 
| Muscle will be examined for histological appearance |  | 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 |  | 6 or 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMD, Duchenne Muscular Dystrophy