Clinical trial NCT00428935: Safety Study of Mini-dystrophin Gene to Treat Duchenne Muscular Dystrophy
Official title: Phase 1 Clinical Trial of rAAV2.5-CMV-mini-Dystrophin Gene Vector in Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne
Muscle
Muscular Dystrophy
Gene Therapy
Dystrophin
Adeno-Associated Virus
AAV
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: AskBio Inc
First posted: 2007-01-30
Enrollment: 6
Sex: MALE
Minimum age (years): 5
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety of a miniature dystrophin gene in the treatment of progressive muscle weakness due to Duchenne Muscular Dystrophy (DMD).

Detailed description: This phase I randomized double blind dose escalation study investigates the safety and efficacy of the mini-dystrophin gene transferred to the biceps muscle for Duchenne muscular dystrophy patients, ages 5 to 12 years of age, using a recombinant adeno-associated virus. Eligible participants must have a known dystrophin gene mutation and may be concurrently treated with corticoid steroids. The mini-dystrophin gene or a placebo agent (normal saline or empty viral capsids) are injected directly into both biceps muscles while under conscious sedation. Following the gene transfer, patients are admitted to the hospital for 48 hours of observation followed by weekly outpatient visits at the Columbus Children's Hospital Neuromuscular Clinic. A bilateral muscle biopsy is preformed following 6 weeks with long term follow up will consisting of bi-annual visits for the next 2 years.

Eligibility criteria: Inclusion Criteria:

* Known null mutation of the Dystrophin gene
* Male age of 5 years or older
* If taking corticosteroids, must have dose unchanged for the past 3 months
* Serum creatine kinase elevation greater than 10x normal value (established by Children's Hospital)
* Progressive, symmetrical proximal muscle weakness of arms and legs

Exclusion Criteria:

* Unable to cooperate for muscle strength testing
* Joint contractures that prohibit muscle strength testing
* Concomitant illness
* Individuals predisposed to excessive vagal responses (bradyarrhythmia or hypotension)
* Controlled substance abuse

Primary outcomes:
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: followed for 2 years post injection
Secondary outcomes:
measure: mini-dystrophin gene expression at the site of gene transfer
timeFrame: 90 days post injection
measure: Maximal Volume Isometric Contraction Testing as a measure of muscle strength
timeFrame: out to 2 years post injection
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Columbus Children's Hospital
state: Ohio
Study officials:
affiliation: Nationwide Children's Hospital
name: Jerry R. Mendell, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Watchko J, O'Day T, Wang B, Zhou L, Tang Y, Li J, Xiao X. Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther. 2002 Aug 10;13(12):1451-60. doi: 10.1089/10430340260185085.
citation: Wang B, Li J, Xiao X. Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13714-9. doi: 10.1073/pnas.240335297.
citation: Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S, Bowles D, Gray S, Li C, Galloway G, Malik V, Coley B, Clark KR, Li J, Xiao X, Samulski J, McPhee SW, Samulski RJ, Walker CM. Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med. 2010 Oct 7;363(15):1429-37. doi: 10.1056/NEJMoa1000228.
citation: Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS, Li J, Wang B, Monahan PE, Rabinowitz JE, Grieger JC, Govindasamy L, Agbandje-McKenna M, Xiao X, Samulski RJ. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther. 2012 Feb;20(2):443-55. doi: 10.1038/mt.2011.237. Epub 2011 Nov 8.