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Retrovirus Vector-Mediated Correction and Cross-Correction of Lysosomal alpha-Mannosidase Deficiency in Human and Feline Fibroblasts
- Source :
- Human Gene Therapy. 10:1311-1319
- Publication Year :
- 1999
- Publisher :
- Mary Ann Liebert Inc, 1999.
-
Abstract
- Lysosomal alpha-mannosidase (EC 3.2.1.24) is an exoglycosidase in the glycoprotein degradation pathway. A deficiency of this enzyme causes the lysosomal storage disease alpha-mannosidosis. Retrovirus vector transfer of a new human alpha-mannosidase cDNA resulted in high-level expression of alpha-mannosidase enzymatic activity in deficient human and feline fibroblasts. The expressed alpha-mannosidase had the same biochemical properties (thermal stability, pH profile, inhibitor/activator sensitivity) as the native enzyme expressed in normal cells. The transferred enzyme colocalized with a control lysosomal hydrolase in cell fractionation experiments. The vector-encoded enzyme also was released at high levels from the corrected cells, and was taken up by untreated mutant cells via the mannose 6-phosphate receptor-mediated endocytic pathway (cross-correction). It is envisioned that genetic correction of a subset of cells (e.g., hematopoietic stem cells) in patients will provide a source of corrective enzyme for other affected tissues in this multisystem disease. Development of a vector expressing high levels of alpha-mannosidase that cross-corrects mutant cells will enable somatic gene transfer experiments in the cat model of human alpha-mannosidosis.
- Subjects :
- Genetic enhancement
Genetic Vectors
Cell Line
Mannosidosis
Mice
Retrovirus
alpha-Mannosidase
Exoglycosidase
Lysosome
Mannosidases
Tumor Cells, Cultured
Genetics
medicine
Lysosomal storage disease
Animals
Humans
Molecular Biology
Glucuronidase
chemistry.chemical_classification
biology
Mucolipidosis
Gene Transfer Techniques
Fibroblasts
biology.organism_classification
medicine.disease
Molecular biology
Retroviridae
Enzyme
medicine.anatomical_structure
chemistry
Biochemistry
Mutation
alpha-Mannosidosis
Cats
Molecular Medicine
Lysosomes
HeLa Cells
Subjects
Details
- ISSN :
- 15577422 and 10430342
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Human Gene Therapy
- Accession number :
- edsair.doi.dedup.....bfb418687e76dbc2eae6136600beb1e1