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Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice

Gene Therapy volume 11, pages 1475–1481 (2004)Cite this article

Abstract

Current therapies for lysosomal storage diseases (LSDs), enzyme replacement therapy and bone marrow transplantation are effective for visceral organ pathology of LSD, but their effectiveness for brain involvement in LSDs is still a subject of controversy. As an alternative approach, we transplanted genetically modified bone marrow stromal (BMS) cells to lateral ventricle of newborn mucopolysaccharidosis VII (MPS VII) mice. MPS VII is one of LSDs and caused by deficiency of beta-glucuronidase (GUSB), resulting in accumulation of glycosaminoglycans (GAGs) in brain. At 2 weeks after transplantation, the GUSB enzyme-positive cells were identified in olfactory bulb, striatum and cerebral cortex, and the enzymatic activities in various brain areas increased. The GAGs contents in brain were reduced to near normal level at 4 weeks after transplantation. Although GUSB activity declined to homozygous level after 8 weeks, the reduction of GAGs persisted for 16 weeks. Microscopic examination indicated that the lysosomal distention was not found in treated animal brain. Cognitive function in MPS VII animals as evaluated by Morris Water Maze test in treated mice showed a marked improvement over nontreated animals. Brain transplantation of genetically modified BMS cells appears to be a promising approach to treat diffuse CNS involvement of LSDs.

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Acknowledgements

We thank Drs DB Kohn (University of Southern California) and WS Sly (Saint Louis University School of Medicine) for kindly providing retrovirus vector and GUSB cDNA, respectively. We thank M Aoki and M Morimatsu of Laboratory Animal Center, The Jikei University School of Medicine, and H Maeda and H Fujita of Seikagaku Corporation for technical assistance. We also thank Dr SU Kim (University of British Columbia) for critical reviewing of this manuscript. This research was supported by the Bio-Venture Research Fund Project grant from the Ministry of Education, Science and Culture of Japan.

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Authors and Affiliations

  1. Department of Gene Therapy, Institute of DNA Medicine, Tokyo, Japan

    K Sakurai, S Iizuka, J-S Shen, X-L Meng, T Ohashi & Y Eto

  2. Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan

    K Sakurai, T Ohashi & Y Eto

  3. Department of Reproductive Biology and Pathology, National Research Institute for Child Health and Development, Tokyo, Japan

    A Umezawa

  4. Department of Pathology, Keio University School of Medicine, Tokyo, Japan

    T Mori

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  1. K Sakurai
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Sakurai, K., Iizuka, S., Shen, JS. et al. Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice. Gene Ther 11, 1475–1481 (2004). https://doi.org/10.1038/sj.gt.3302338

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