Clinical trial NCT02704325: Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2
Official title: Phase I Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: DMD
Duchenne Muscular Dystrophy
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
First posted: 2016-03-10
Enrollment: 0
Sex: MALE
Minimum age (years): 9
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment related toxicities
timeFrame: 2 years
Secondary outcomes:
measure: Expression of GALGT2 demonstrated with anti-CT epitope antibodies.
timeFrame: 6 or 12 weeks
measure: GALGT2 protein expression quantified by western blot and assessed by densitometry
timeFrame: 6 or 12 weeks
measure: Transduction efficiency measured by qPCR of the GALGT transgene from muscle, and expressed as vector genomes normalized to a genomic single-copy control.
timeFrame: 6 or 12 weeks
measure: Number of fibers containing central nuclei compared between muscles by paired t-tests
timeFrame: 6 or 12 weeks
measure: Dystrophin expression demonstrated with antibodies to N-terminal, C-terminal, and rod domains
timeFrame: 6 or 12 weeks
measure: Utrophin expression
timeFrame: 6 or 12 weeks
measure: Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387
timeFrame: 6 or 12 weeks
measure: Muscle will be examined for histological appearance
timeFrame: 6 or 12 weeks
measure: Antibodies to rAAVrh74 along with PBMC ELISpots to both rAAVrh74 capsid and GALGT protein will be evaluated at different time points during the study
timeFrame: 6 or 12 weeks
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
Study officials:
affiliation: Nationwide Children's Hospital
name: Kevin Flanigan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chicoine LG, Rodino-Klapac LR, Shao G, Xu R, Bremer WG, Camboni M, Golden B, Montgomery CL, Shontz K, Heller KN, Griffin DA, Lewis S, Coley BD, Walker CM, Clark KR, Sahenk Z, Mendell JR, Martin PT. Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin alpha2 surrogates. Mol Ther. 2014 Apr;22(4):713-24. doi: 10.1038/mt.2013.246. Epub 2013 Oct 22.
citation: Martin PT, Xu R, Rodino-Klapac LR, Oglesbay E, Camboni M, Montgomery CL, Shontz K, Chicoine LG, Clark KR, Sahenk Z, Mendell JR, Janssen PM. Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice. Am J Physiol Cell Physiol. 2009 Mar;296(3):C476-88. doi: 10.1152/ajpcell.00456.2008. Epub 2008 Dec 24.