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Long-Term Expression in Genetic Disease: In Vivo Gene Transfer with Recombinant Adeno-Associated Viral (AAV) Vectors Recombinant AAV vectors have emerged as attractive gene delivery vehicles for genetic disease. Engineered from a small replication-defective DNA virus, they are devoid of viral coding sequences and trigger very little immune response in experimental animals. They are capable of transducing nondividing target cells, and the donated DNA is stabilized primarily in an episomal form, thus minimizing risks associated with insertional mutagenesis. Because the vector has a tropism for certain long-lived cell types, such as skeletal muscle, the central nervous system (CNS), and hepatocytes, long-term. | Chapter 065. Gene Therapy in Clinical Medicine Part 3 Long-Term Expression in Genetic Disease In Vivo Gene Transfer with Recombinant Adeno-Associated Viral AAV Vectors Recombinant AAV vectors have emerged as attractive gene delivery vehicles for genetic disease. Engineered from a small replication-defective DNA virus they are devoid of viral coding sequences and trigger very little immune response in experimental animals. They are capable of transducing nondividing target cells and the donated DNA is stabilized primarily in an episomal form thus minimizing risks associated with insertional mutagenesis. Because the vector has a tropism for certain long-lived cell types such as skeletal muscle the central nervous system CNS and hepatocytes long-term expression can be achieved even in the absence of integration. Clinical trials using recombinant AAV vectors are now ongoing for muscular dystrophies ai-antitrypsin deficiency lipoprotein lipase deficiency hemophilia B and a form of congenital blindness called Leber s congenital amaurosis. Hemophilia is often considered a promising disease model for gene transfer as the gene product does not require precise regulation of expression and biologically active clotting factors can be synthesized in a variety of tissue types permitting latitude in choice of target tissue. Moreover raising circulating factor levels from 1 levels seen in those severely affected into the range of 5 greatly improves the phenotype of the disease. Preclinical studies with recombinant AAV vectors infused into skeletal muscle or liver have resulted in long-term 5 years expression of factor VIII or factor IX in the hemophilic dog model. Administration to skeletal muscle of an AAV vector expressing factor IX in patients with hemophilia was safe and resulted in long-term expression as measured by muscle biopsy but circulating levels never rose 1 for sustained periods and a large number of IM injections 80-100 was required to access a large muscle mass. .
