Duchenne Muscular Dystrophy
Conditions
Keywords
DMD, Duchenne Muscular Dystrophy
Brief summary
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
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.
Interventions
BIOLOGICALrAAVrh74.MCK.GALGT2
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.
OTHERPLACEBO (Saline)
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.
Sponsors
Kevin Flanigan
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
MALE
Age
9 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment related toxicities | 2 years | Based on the development of unacceptable toxicity defined as the occurrence of any one Grade III or higher treatment-related toxicities. |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Muscle will be examined for histological appearance | 6 or 12 weeks |
| Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387 | 6 or 12 weeks |
| Expression of GALGT2 demonstrated with anti-CT epitope antibodies. | 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 |
| Utrophin expression | 6 or 12 weeks |
Countries
United States
Outcome results
None listed