Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis

Authors

  • Shannon L. Macauley PhD,

    1. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO
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  • Marie S. Roberts BA,

    1. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO
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  • Andrew M. Wong PhD,

    1. Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, United Kingdom
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  • Francesca McSloy BSc,

    1. Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, United Kingdom
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  • Adarsh S. Reddy MD, PhD,

    1. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO
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  • Jonathan D. Cooper PhD,

    1. Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, United Kingdom
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  • Mark S. Sands PhD

    Corresponding author
    1. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO
    2. Department of Genetics, Washington University School of Medicine, St Louis, MO
    • Washington University School of Medicine, Department of Internal Medicine, Campus Box 8007, 660 S. Euclid Ave., St Louis, MO 63110
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Abstract

Objective:

Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited childhood neurodegenerative disorder caused by the loss of palmitoyl protein thioesterase-1 (PPT1) activity. Affected children suffer from blindness, epilepsy, motor dysfunction, cognitive decline, and premature death. The Ppt1−/− mouse shares the histological and clinical features of INCL. Previous single-therapy approaches using small molecule drugs, gene therapy, or neuronal stem cells resulted in partial histological correction, with minimal improvements in motor function or lifespan. Here, we combined central nervous system (CNS)-directed adeno-associated virus (AAV)2/5-mediated gene therapy with bone marrow transplantation (BMT) in the INCL mouse.

Methods:

At birth, Ppt1−/− and wild-type mice were given either intracranial injections of AAV2/5-PPT1 or bone marrow transplantation, separately as well as in combination. To assess function, we measured rotorod performance monthly as well as lifespan. At terminal time points, we evaluated the therapeutic effects on several INCL-specific parameters, such as cortical thickness, autofluorescent accumulation, and glial activation. Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment in treated mice.

Results:

AAV2/5-mediated gene therapy alone resulted in significant histological correction, improved motor function, and increased lifespan. Interestingly, the addition of BMT further increased the lifespan of treated mice and led to dramatic, sustained improvements in motor function. These data are truly striking, given that BMT alone is ineffective, yet it synergizes with CNS-directed gene therapy to dramatically increase efficacy and lifespan.

Interpretation:

AAV2/5-mediated gene therapy in combination with BMT provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters. ANN NEUROL 2012;

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