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Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins

Authors

  • Jerry R. Mendell MD,

    Corresponding author
    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Department of Neurology, the Ohio State University, Columbus, OH
    4. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
    • Research Institute at Nationwide Children's Hospital, 700 Children's Dr. Room WA3011, Columbus, OH 43235
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  • Louise R. Rodino-Klapac PhD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Xiomara Rosales-Quintero MD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Janaiah Kota PhD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Brian D. Coley MD,

    1. Nationwide Children's Hospital, Columbus, OH
    2. Department of Radiology, the Ohio State University, Columbus, OH
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  • Gloria Galloway MD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Josepha M. Craenen MD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
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  • Sarah Lewis,

    1. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Vinod Malik PhD,

    1. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Christopher Shilling MS,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Barry J. Byrne MD, PhD,

    1. Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
    2. Powell Gene Therapy Center, Gainesville, FL
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  • Thomas Conlon PhD,

    1. Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
    2. Powell Gene Therapy Center, Gainesville, FL
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  • Katherine J. Campbell,

    1. Center for Vaccines and Immunity, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • William G. Bremer,

    1. Center for Vaccines and Immunity, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Laurence Viollet PhD,

    1. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Christopher M. Walker PhD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Vaccines and Immunity, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Zarife Sahenk MD, PhD,

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Department of Neurology, the Ohio State University, Columbus, OH
    4. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • K. Reed Clark PhD

    1. Department of Pediatrics, the Ohio State University, Columbus, OH
    2. Nationwide Children's Hospital, Columbus, OH
    3. Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Potential conflict of interest: Nothing to report.

  • This study has been registered at Clinicaltrials.gov NCT00494195.

Abstract

Objective

α-Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb-girdle muscular dystrophy type 2D [LGMD2D]) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy and persistence of gene expression.

Methods

A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis muscle was conducted. Control sides received saline. A 3-day course of methylprednisolone accompanied gene transfer without further immune suppression.

Results

No adverse events were encountered. SGCA gene expression increased 4–5-fold over control sides when examined at 6 weeks (2 subjects) and 3 months (1 subject). The full sarcoglycan complex was restored in all subjects, and muscle fiber size was increased in the 3-month subject. Adeno-associated virus serotype 1 (AAV1)-neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found, but showed features of programmed cell death. Enzyme-linked immunospot (ELISpot) showed no interferon-γ response to α-SG or AAV1 capsid peptide pools, with the exception of a minimal capsid response in 1 subject. Restimulation to detect low-frequency capsid-specific T cells by ELISpot assays was negative. Results of the first 3 subjects successfully achieved study aims, precluding the need for additional enrollment.

Interpretation

The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials. Ann Neurol 2009;66:290–297

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