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The Journal of Neuroscience, November 24, 2004, 24(47):10642-10651; doi:10.1523/JNEUROSCI.3584-04.2004

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Neurobiology of Disease
Intracerebral Transplantation of Adult Mouse Neural Progenitor Cells into the Niemann-Pick-A Mouse Leads to a Marked Decrease in Lysosomal Storage Pathology

L. S. Shihabuddin,¹ S. Numan,² M. R. Huff,¹ J. C. Dodge,¹ J. Clarke,¹ S. L. Macauley,¹ W. Yang,¹ T. V. Taksir,¹ G. Parsons,¹ M. A. Passini,¹ F. H. Gage,³ and G. R. Stewart¹

¹Genzyme Corporation, Framingham, Massachusetts 01701, ²Department of Neurology, University of Cincinnati, Cincinnati, Ohio 45267, and ³Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037

Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. In the present study, we evaluated the effects of direct intracerebral transplantation of neural progenitor cells (NPCs) on the brain storage pathology in the ASM knock-out (ASMKO) mouse model of Type A Niemann-Pick disease. NPCs derived from adult mouse brain were genetically modified to express human ASM (hASM) and were transplanted into multiple regions of the ASMKO mouse brain. Transplanted NPCs survived, migrated, and showed region-specific differentiation in the host brain up to 10 weeks after transplantation (the longest time point examined). In vitro, gene-modified NPCs expressed up to 10 times more and released five times more ASM activity into the culture media compared with nontransduced NPCs. In vivo, transplanted cells expressed hASM at levels that were barely detectable by immunostaining but were sufficient for uptake and cross-correction of host cells, leading to reversal of distended lysosomal pathology and regional clearance of sphingomyelin and cholesterol storage. Within the host brain, the area of correction closely overlapped with the distribution of the hASM-modified NPCs. No correction of pathology occurred in brain regions that received transplants of nontransduced NPCs. These results indicate that the presence of transduced NPCs releasing low levels of hASM within the ASMKO mouse brain is necessary and sufficient to reverse lysosomal storage pathology. Potentially, NPCs may serve as a useful gene transfer vehicle for the treatment of CNS pathology in other lysosomal storage diseases and neurodegenerative disorders.

Key words: neural progenitor cell; transplantation; metabolic; neurodegenerative; storage; repair

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Received June 8, 2004; accepted October 8, 2004.

This article has been cited by other articles:

				M. A. Passini, J. Bu, J. A. Fidler, R. J. Ziegler, J. W. Foley, J. C. Dodge, W. W. Yang, J. Clarke, T. V. Taksir, D. A. Griffiths, et al. Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse PNAS, May 29, 2007; 104(22): 9505 - 9510. [Abstract] [Full Text] [PDF]

				J. C. Dodge, J. Clarke, A. Song, J. Bu, W. Yang, T. V. Taksir, D. Griffiths, M. A. Zhao, E. H. Schuchman, S. H. Cheng, et al. Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease PNAS, December 6, 2005; 102(49): 17822 - 17827. [Abstract] [Full Text] [PDF]

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