Viral-mediated delivery of the late-infantile neuronal ceroid lipofuscinosis gene, TPP-I to the mouse central nervous system
- 1 January 2003
- journal article
- Published by Springer Nature in Gene Therapy
- Vol. 10 (1) , 34-42
- https://doi.org/10.1038/sj.gt.3301843
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 beta-galactosidase-expressing adenovirus vector (AdTTP-I/nlsbetagal) was used to distinguish transduced (beta-galactosidase positive) cells from cells that endocytosed secreted TTP-I. Ten days after striatal injection of AdTTP-I/nlsbetagal, beta-galactosidase-positive cells were concentrated around the injection site, corpus callosum, ependyma and choroid plexus. In cerebellar injections, beta-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 beta-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.Keywords
This publication has 25 references indexed in Scilit:
- Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectorsProceedings of the National Academy of Sciences, 2002
- The HIV Tat protein transduction domain improves the biodistribution of β-glucuronidase expressed from recombinant viral vectorsNature Biotechnology, 2001
- Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosisBiochemical Journal, 2001
- In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected miceNature Medicine, 2001
- The Human CLN2 Protein/Tripeptidyl-Peptidase I Is a Serine Protease That Autoactivates at Acidic pHJournal of Biological Chemistry, 2001
- Reversal of Pathology in the Entire Brain of Mucopolysaccharidosis Type VII Mice after Lentivirus-Mediated Gene TransferHuman Gene Therapy, 2000
- Recombinant adeno-associated virus type 2, 4, and 5 vectors: Transduction of variant cell types and regions in the mammalian central nervous systemProceedings of the National Academy of Sciences, 2000
- Extensiveβ-Glucuronidase Activity in Murine Central Nervous System after Adenovirus-Mediated Gene Transfer to BrainHuman Gene Therapy, 1998
- Association of Mutations in a Lysosomal Protein with Classical Late-Infantile Neuronal Ceroid LipofuscinosisScience, 1997
- Mitochondrial ATP synthase subunit c storage in the ceroid‐lipofuscinoses (Batten disease)American Journal of Medical Genetics, 1992