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Viral-mediated delivery of the late-infantile neuronal ceroid lipofuscinosis gene, TPP-I to the mouse central nervous system

Gene Therapy volume 10, pages 34–42 (2003)Cite this article

Abstract

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is caused by mutations in tripeptidyl peptidase I (TPP-I), a pepstatin-insensitive lysosomal protease, resulting in neurodegeneration, acute seizures, visual and motor dysfunction. In vitro studies suggest that TPP-I is secreted from cells and subsequently taken up by neighboring cells, similar to other lysosomal enzymes. As such, TPP-I is an attractive candidate for enzyme replacement or gene therapy. In the present studies, we examined the feasibility of gene transfer into mouse brain using recombinant adenovirus (Ad), feline immunodeficiency virus (FIV) and adeno-associated virus (AAV) vectors expressing TPP-I, after single injections into the striatum or cerebellum. A dual TPP-I- and β-galactosidase-expressing adenovirus vector (AdTTP-I/nlsβgal) was used to distinguish transduced (β-galactosidase positive) cells from cells that endocytosed secreted TTP-I. Ten days after striatal injection of AdTTP-I/nlsβgal, β-galactosidase-positive cells were concentrated around the injection site, corpus callosum, ependyma and choroid plexus. In cerebellar injections, β-galactosidase expression was confined to the region of injection and in isolated neurons of the brainstem. Immunohistochemistry for TPP-I expression showed that TPP-I extended beyond areas of β-galactosidase activity. Immunohistochemistry for TTP-I after FIVTTP-I and AAV5TTP-I injections demonstrated TPP-I in neurons of the striatum, hippocampus and Purkinje cells. For all three vectors, TPP-I activity in brain homogenates was 3–7-fold higher than endogenous levels in the injected hemispheres. Our results indicate the feasibility of vector-mediated gene transfer of TPP-I to the CNS as a potential therapy for LINCL.

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Acknowledgements

The authors thank Dr Istvan Sohar and Dr Peter Lobel for assistance with the TPP-I activity assays, Dr Sybille Sauter for the FIVTPP plasmid, Inês Martins and Ken Ratliff for excellent technical assistance and Drs Colleen Stein and Jason Heth for critical discussions. We also thank the University of Iowa Gene Transfer Vector Core (DK 54759) for help with virus production. This work was supported in part by a grant from the Batten Disease Support and Research Association (BDSRA), and from the Roy J. Carver Trust (BLD).

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Author notes

  1. R E Haskell and S M Hughes: The first two authors contributed equally

Authors and Affiliations

  1. Department of Internal Medicine, Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, IA, USA

    R E Haskell, S M Hughes, J M Alisky & B L Davidson

  2. National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    J A Chiorini

  3. Department of Neurology, Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, IA, USA

    B L Davidson

  4. Department of Physiology & Biophysics, Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, IA, USA

    B L Davidson

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  1. R E Haskell
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  4. J M Alisky
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Haskell, R., Hughes, S., Chiorini, J. et al. Viral-mediated delivery of the late-infantile neuronal ceroid lipofuscinosis gene, TPP-I to the mouse central nervous system. Gene Ther 10, 34–42 (2003). https://doi.org/10.1038/sj.gt.3301843

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