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Original Article
Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis
Article first published online: 24 FEB 2012
DOI: 10.1002/ana.23545
Copyright © 2012 American Neurological Association
Additional Information
How to Cite
Macauley, S. L., Roberts, M. S., Wong, A. M., McSloy, F., Reddy, A. S., Cooper, J. D. and Sands, M. S. (2012), Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis. Ann Neurol., 71: 797–804. doi: 10.1002/ana.23545
Publication History
- Issue published online: 20 JUN 2012
- Article first published online: 24 FEB 2012
- Accepted manuscript online: 1 FEB 2012 07:20AM EST
- Manuscript Accepted: 13 JAN 2012
- Manuscript Revised: 16 DEC 2011
- Manuscript Received: 16 NOV 2011
Funded by
- the NIH Neurologic Disease and Stroke. Grant Number: (NS043105; M.S.S.)
- Ruth L. Kirschstein National Research Service Award Fellowship. Grant Number: (NS056728; S.L.M.)
- Wellcome Trust. Grant Number: (GR079491MA; J.D.C., A.M.W., F.M.)
- Batten Disease Family Association (J.D.C., A.M.W., F.M.)
- Batten Disease Support and Research Association (J.D.C., A.M.W., F.M., S.L.M., M.S.S.)
- Bletsoe Family (J.D.C., A.M.W.)
- NIH National Institute of Neurological Disorders and Stroke (J.D.C., F.M., A.M.W.)
- National Tay Sachs and Allied Diseases Foundation (A.S.R.)
- Abstract
- Article
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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;