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

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. There will be a modified intravascular limb infusion (ILI) procedure that will be used to sequentially deliver vector to each whole lower limb of DMD subjects via a major lower limb artery.

Detailed Description
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This is an open-label, dose escalation trial where the vector will be delivered via the femoral artery to the muscles of both legs of DMD subjects. The primary objective of this study is the assessment of the safety of intravascular administration of rAAVrh74.MCK.GALGT2 to DMD patients. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and GALGT2, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcome for this disorder including a combination of functional 6 minute walk test (6MWT) and direct muscle testing for strength (MVICT) of lower limb muscles. Subjects will be evaluated at baseline, infusion visit (days 0-2), and return for follow up visits on days 7, 14, 30, 60, 90, and 180 and months 12, 18 and 24

Official Title
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Phase I/IIa 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Ambulant patients age 4 years or older Confirmed mutations in the DMD gene using a clinical accepted technique that completely defines the mutation 1,2 • Measurably impaired muscle function (defined as less than 80% of the predicted value for 100 MWT), but with sufficient muscle preservation to ensure assessment of muscle transfection based on clinical evaluation by the PI and expert colleagues. This degree of preservation will include: Ability to extend the knee fully against gravity Preserved ambulation with ability to walk ≥ 350 meters during the 6MWT A magnetic resonance image of the quadriceps showing preservation of sufficient muscle mass to permit transfection Males of any ethnic group will be eligible Ability to cooperate with muscle testing Stable daily dose of corticosteroid therapy (including either prednisone, prednisolone, deflazacort or 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 Subject is amenable to or is currently being treated with eteplirsen 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 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 ≥ 1:50 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: 4 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: Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2<br>N = 3 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] | Biological: rAAVrh74.MCK.GALGT2<br>* Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)<br>|
| Experimental: Cohort 2 (Dose Escalation) rAAVrh74.MCK.GALGT2<br>N=3 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] | Biological: rAAVrh74.MCK.GALGT2<br>* Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Unanticipated Grade III or Higher Treatment-Related Toxicities |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2). | Percentage of fibers expressing GALGT2 in each biopsy sample. | Day 90 (Cohort 2) and Day 120 (Cohort 1) | 
| GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2) |  | Day 90 (Cohort 2) and Day 120 (Cohort 1) | 

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