セッション情報 International Session2(肝臓学会・消化器病学会合同)

Gene therapy and cell therapy through the liver; current aspects and future prospects

タイトル 肝IS2-4指:

A next generation sequencing (NGS)-based approach toward developing new adeno-associated virus (AAV) vectors for gene therapy

演者 H. Nakai(Department of Molecular & Medical Genetics, Oregon Health & Science University)
共同演者
抄録 AAV vectors are among the most attractive gene delivery vehicles for human gene therapy. Promising therapeutic efficacy of AAV gene therapy has been reported in several clinical trials, including liver-targeted hemophilia B trials. However, further improvements of AAV vectors will be required for making AAV gene therapy a more effective and common practice. Although such improvements would be possible by AAV capsid engineering, this has been hindered by a paucity of knowledge about the AAV capsid structure-function relationships. To overcome this limitation, we have established a novel NGS-based approach that allows streamlined, high-throughput characterization of a wide spectrum of phenotypes of hundreds of different AAV species. This approach enables the collection of a large dataset on AAV capsid amino acid sequence-phenotype relationships by using comprehensive AAV serotype and capsid mutant libraries in which each AAV species is tagged with species-specific DNA barcodes placed within the viral genome. We have applied this approach to cultured cells, wild-type mice, FRG mice with humanized liver, and rhesus macaques, which has allowed us to build a comprehensive, intellectual foundation of engineering novel AAV capsids. To date, we have elucidated a series of previously unidentified, but functionally important capsid amino acids including those responsible for hepatic transduction; and have found that hepatic tropism of certain AAV species is significantly different between rodents and primates.
索引用語 gene therapy, adeno-associated virus