A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells.
A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells.
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一项对患有 A 型血友病的狗进行 AAV 基因治疗的长期研究确定了转导肝细胞的克隆扩增。
DOI：
10.1038/s41587-020-0741-7
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发表时间：
2021-01
影响因子：
46.9
通讯作者：
Sabatino DE
中科院分区：
文献类型：
--
作者：
Nguyen GN;Everett JK;Kafle S;Roche AM;Raymond HE;Leiby J;Wood C;Assenmacher CA;Merricks EP;Long CT;Kazazian HH;Nichols TC;Bushman FD;Sabatino DE
9只A型血友病犬接受腺相关病毒（AAV）基因治疗，随访10年。给予表达犬因子VIII （AAV-cFVIII）的AAV8或AAV9载体将FVIII缺乏症纠正为正常FVIII水平的1.9% - 11.3%。在9只狗中的2只，FVIII活性在治疗后大约4年开始逐渐增加。没有狗显示出肿瘤或肝功能改变的迹象。对6只接受治疗的狗的肝脏样本中的整合位点进行分析，在5只狗的基因组DNA和扩增的细胞克隆中发现了1741个独特的AAV整合事件，其中44%的整合靠近与细胞生长有关的基因。所有恢复的集成向量被部分删除和/或重新排列。我们的数据表明，两只狗中FVIII蛋白表达的增加可能是由于携带整合载体的细胞的克隆扩增。这些结果支持肝定向AAV基因治疗A型血友病的临床发展，同时强调长期监测潜在遗传毒性的重要性。在血友病A犬的AAV基因治疗研究中发现转导细胞克隆扩增。
Nine hemophilia A dogs were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9%−11.3% of normal FVIII levels. In two of nine dogs, FVIII activity increased gradually starting about four years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of these integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A while emphasizing the importance of long-term monitoring for potential genotoxicity. An AAV gene therapy study in hemophilia A dogs finds clonal expansions of transduced cells.
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影响因子：
15.9
作者：
Chandler, Randy J.;LaFave, Matthew C.;Venditti, Charles P.
通讯作者：
Venditti, Charles P.
DOI：
10.1073/pnas.192219599
发表时间：
2002-10-01
影响因子：
11.1
作者：
Lozier, JN;Dutra, A;Morgan, RA
通讯作者：
Morgan, RA
影响因子：
56.9
作者：
Donsante, Anthony;Miller, Daniel G.;Sands, Mark S.
通讯作者：
Sands, Mark S.
影响因子：
24.5
作者：
La Bella, Tiziana;Imbeaud, Sandrine;Zucman-Rossi, Jessica
通讯作者：
Zucman-Rossi, Jessica
影响因子：
5.1
作者：
Donsante, A;Vogler, C;Sands, MS
通讯作者：
Sands, MS