Clinical trial NCT02710500: rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies
Official title: Phase I Intramuscular Gene Transfer Clinical Trial for Dysferlin Deficiency Delivering the Dysferlin Gene by AAVrh74
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Dysferlinopathy
Keywords: LGMD2B
Limb Girdle Muscular Dystrophy
Miyoshi
Gene Transfer
Dysferlin
Lead sponsor: Sarepta Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2016-03-16
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The proposed clinical trial is a double-blind, randomized controlled study with direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV gene vector to the extensor digitorum brevis muscle (EDB). Two cohorts of subjects with dysferlin deficiency, each with proven mutations will undergo gene transfer. A minimum of three subjects will be enrolled into each cohort.

Detailed description: This is a phase I safety and tolerability study with a direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV transferred to the extensor digitorum brevis muscle (EDB). The study is designed as a randomized, controlled, dose escalation trial with one EDB receiving the rAAVrh.74.MHCK7.DYSF.DV and the other side receiving saline alone. It will follow the previously safe and effective IM gene transfer to EDB for LGMD2D.2, 3 The first cohort, inclusive of three Dysferlinopathy subjects, will receive a gene transfer total dose of 2 x 10\^12 vector genomes. Muscle biopsies will be performed at Day 45 (two subjects) and Day 90 (one subject). If there are no safety concerns, three additional subjects will be enrolled and receive an escalated dose at 6 X 10\^12 vg (total dose). Muscle biopsies in the second cohort will be performed at Day 90 (one subject) and Day 180 (two subjects). This protocol design gives us a maximum period of observation ranging from 6 weeks to 6 months to capture both transient and delayed gene expression, and to recognize sustained expression.

Eligibility criteria: Inclusion Criteria:

* Must be Non-ambulant (cannot walk 10 meters in ≤ 30 sec) and age 18 years or older
* Established mutations of the dysferlin gene on both alleles
* Impaired muscle function but with sufficient muscle preservation to ensure muscle transfection based on magnetic resonance image of the EDB showing sufficient muscle preservation to permit transfection
* Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene transfer (females) or until two negative sperm samples are obtained post gene transfer (males).

Exclusion Criteria:

* Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis A, B or C infection
* The presence of a Dysferlin mutations 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%
* 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
* Pregnancy
* AAVrh74 or AAV8 binding antibody titers \> 1:50 as determined by ELISA immunoassay
* Abnormal laboratory values in the clinically significant range in the table below, based upon normal values in the Nationwide Children's Hospital Laboratory: GGT, Total Bilirubin, Cystatine, Hemoglobin, White Blood Cells

Primary outcomes:
measure: Determination of safety based on the development of unacceptable toxicity
timeFrame: 2 Years
Secondary outcomes:
measure: Number of participants showing dysferlin protein expression in muscle tissue
timeFrame: 2 Years
measure: Leukocyte marker counts including CD45, CD3, CD4, CD8, and MAC 387.
timeFrame: 2 Years
measure: Binding antibodies counts and ELISpot counts to both rAAVrh74 capsid and dysferlin protein.
timeFrame: 2 Years
measure: Number of inflammatory cells in muscle
timeFrame: 2 Years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hosptial
state: Ohio
Study officials:
affiliation: Director, Center for Gene Therapy
name: Jerry R Mendell, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sondergaard PC, Griffin DA, Pozsgai ER, Johnson RW, Grose WE, Heller KN, Shontz KM, Montgomery CL, Liu J, Clark KR, Sahenk Z, Mendell JR, Rodino-Klapac LR. AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models. Ann Clin Transl Neurol. 2015 Mar;2(3):256-70. doi: 10.1002/acn3.172. Epub 2015 Jan 20.
citation: Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR. Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One. 2012;7(6):e39233. doi: 10.1371/journal.pone.0039233. Epub 2012 Jun 15.