Background: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical\nstudies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also\nidentified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T\nlymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other\nstrategies to reduce capsid antigen presentation are desirable.\nMethods: We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B\nby hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated\nthrough molecular evolution.\nResults: AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation\nFIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however,\nexpression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC\ncapsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog.\nConclusions: Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in\nhepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict\nefficacy in other species and thus is of limited translational utility.
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