Clinical Trial: rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Phase I Intramuscular Gene Transfer Clinical Trial for Dysferlin Deficiency Delivering the Dysferlin Gene by AAVrh74

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 Summary: 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.
Sponsor: Nationwide Children's Hospital

Current Primary Outcome: Determination of safety based on the development of unacceptable toxicity [ Time Frame: 2 Years ]

Defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Number of participants showing dysferlin protein expression in muscle tissue [ Time Frame: 2 Years ]

    More than 3 fold increase in dysferlin protein expression in muscle compared to control side by western blot or more than 30% increase in dysferlin-expressing fibers

    Dysferlin protein expression as demonstrated with N -terminal anti-dysferlin antibodies will be quantified using BioQuant

  • Leukocyte marker counts including CD45, CD3, CD4, CD8, and MAC 387. [ Time Frame: 2 Years ]
    Number of CD4+ cells/ mm2 area; Number of CD8+ cells/ mm2 area; Number of muscle fibers expressing MHCI staining / mm2 area; Number of muscle fibers expressing MHCII staining / mm2 area
  • Binding antibodies counts and ELISpot counts to both rAAVrh74 capsid and dysferlin protein. [ Time Frame: 2 Years ]
    AAVrh74 or AAV8 binding antibody titers > 1:50 as determined by ELISA immunoassay
  • Number of inflammatory cells in muscle [ Time Frame: 2 Years ]
    Number of inflammatory cells per mm2 area


Original Secondary Outcome: Same as current

Information By: Nationwide Children's Hospital

Dates:
Date Received: February 11, 2016
Date Started: March 2016
Date Completion: March 2018
Last Updated: November 21, 2016
Last Verified: November 2016