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Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Gene Therapy volume 12, pages 1145–1153 (2005)Cite this article

Abstract

With the ultimate goal of developing a novel treatment for multiple sclerosis (MS), we have developed a cell-based gene therapy protocol for the treatment of murine experimental autoimmune encephalomyelitis (EAE), a powerful animal model for MS. We have determined that transduced fibroblasts secreting encephalogenic epitopes, when injected into mice with EAE, cause a striking abrogation of disease. Both myelin basic protein (MBP) and proteolipid protein mini-gene constructs expressed in syngeneic fibroblast cells were capable of ameliorating ongoing EAE induced by MBP protein. These experiments are crucial since they suggest that not all encephalogenic epitopes need be secreted for the control of disease. We also demonstrate the success of this protocol when transduced syngeneic, and most importantly, allogeneic cells are sequestered within an implantable chamber. Furthermore, we find that through modifying antigen expression by changing the signal sequence of the mini-gene construct, we were able to significantly reduce the dose of cells required for treatment. These improvements to the mini-gene delivery system are critical for the eventual translation of our protocol to the clinic.

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Acknowledgements

We thank Drs French Anderson (USC), Wendy Gilmore (USC), and Brett Lund (USC) for helpful discussions. We also thank Ray Ortiz (DDF Services) for histology sectioning and staining of the chamber, Dr David Hinton (USC) for photomicrographs, Scott Fredericksen (TheraCyte) for advice on chamber handling, and Bruce Hess (Corixa) for production of retroviral particles. We acknowledge the USC/Norris Cancer Center Microchemistry Core Facility for the synthesis of peptides and oligonucleotides, and for automated DNA sequencing. This study was funded by grants from the National Institutes of Health (R01 NS35240, LPW), the National Multiple Sclerosis Society (PP0535, MM), the Conrad Hilton Foundation, the Nancy Davis Foundation, the Kenneth Norris Foundation, and Corixa Corporation. We are grateful to Holly Weisbuch for manuscript preparation and editorial support.

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Authors and Affiliations

  1. Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    K A Louie, L P Weiner, J Du, H H Kochounian, W Wei & M McMillan

  2. Department of Microbiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    K A Louie, L P Weiner, H H Kochounian & M McMillan

  3. Corixa Corporation, Seattle, WA, USA

    S P Fling

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Louie, K., Weiner, L., Du, J. et al. Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis. Gene Ther 12, 1145–1153 (2005). https://doi.org/10.1038/sj.gt.3302503

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