In Vivo Treatment of Hemophilia A and Mucopolysaccharidosis Type VII Using Nonprimate Lentiviral Vectors
| Autor: | Jiahua Qian, Yubin Kang, Todd A. Derksen, Beverly L. Davidson, Inês Martins, Patrick D. Staber, Sybille L. Sauter, Kay Townsend, Paul B. McCray, Colleen S. Stein |
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| Rok vydání: | 2001 |
| Předmět: |
Feline immunodeficiency virus
Genetic enhancement Transgene Mucopolysaccharidosis Genetic Vectors Spleen Immunodeficiency Virus Feline Hemophilia A Viral vector Mice Transduction (genetics) In vivo Drug Discovery Genetics medicine Animals Molecular Biology DNA Primers Glucuronidase Mice Knockout Pharmacology Factor VIII biology Reverse Transcriptase Polymerase Chain Reaction Gene Transfer Techniques Mucopolysaccharidosis VII Defective Viruses Genetic Therapy biology.organism_classification medicine.disease Virology Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Injections Intravenous Immunology Molecular Medicine |
| Zdroj: | Molecular Therapy. 3:850-856 |
| ISSN: | 1525-0016 |
| DOI: | 10.1006/mthe.2001.0325 |
| Popis: | Gene therapy holds great promise for the treatment of a variety of inherited diseases, including hemophilia A and mucopolysaccharidosis type VII (MPS VII). In both these disorders, subnormal levels of replacement protein have therapeutic effects. Thus we hypothesized that transduction of a small proportion of cells by feline immunodeficiency virus (FIV)-based lentiviral vectors might provide sufficient levels of transgene expression for phenotypic correction. We intravenously injected replication-deficient FIV-based vectors encoding either human factor VIII or human β-glucuronidase into factor VIII-deficient or β-glucuronidase-deficient mice, respectively. This route of delivery targeted multiple organs, with the liver as the primary transduction site. In the hemophilia A mice, factor VIII expression persisted for the duration of the experiments (approximately 5 months), and recipient mice survived an otherwise lethal bleeding episode (tail-clipping). In mucopolysaccharidosis type VII mice, substantial β-glucuronidase activity was detected in several tissues and corresponded with marked reduction of lysosomal storage in liver and spleen. These findings indicate that gene transfer with FIV-based lentiviral vectors can permanently introduce transgenes into a sufficient number of hepatocytes for long-term therapeutic effect and suggest potential clinical value of FIV-based lentiviral vectors for treatment of hemophilia A and MPS VII. |
| Databáze: | OpenAIRE |
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