A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice

被引:201
作者
Brown, Brian D. [1 ]
Cantore, Alessio [1 ]
Annoni, Andrea [1 ]
Sergi, Lucia Sergi [1 ]
Lombardo, Angelo [1 ]
Della Valle, Patrizia [2 ]
D'Angelo, Armando [2 ]
Naldini, Luigi [1 ,3 ]
机构
[1] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy
[2] Hosp San Raffaele, IRCCS, Fdn Ctr San Raffaele Del Monte Tabor, Coagulat Serv & Thrombosis Res Unit, I-20132 Milan, Italy
[3] Univ Vita Salute San Raffaele, Milan, Italy
关键词
D O I
10.1182/blood-2007-03-078493
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A longstanding goal for the treatment of hemophilia B is the development of a gene transfer strategy that can maintain sustained production of clotting factor IX (FIX) in the absence of an immune response. To this end, we have sought to use lentiviral vectors (LVs) as a means for systemic gene transfer. Unfortunately, initial evaluation of LVs expressing F.IX from hepatocyte-specific promoters failed to achieve sustained F.IX expression in hemophilia B mice due to the induction of an anti-F.IX cellular immune response. Further analysis suggested that this may be a result of off-target transgene expression in hematopoietic-lineage cells of the spleen. In order to overcome this problem, we modified our vector to contain a target sequence for the hematopoietic-specific microRNA, miR-142-3p. This eliminated off-target expression in hematopoietic cells, and enabled sustained gene transfer in hemophilia B mice for more than 280 days after injection. Treated mice had more than 10% normal F.IX activity, no detectable anti-F.IX antibodies, and were unresponsive to F.IX immunization. Importantly, the mice survived tail-clip challenge, thus demonstrating phenotypic correction of their bleeding diathesis. This work, which is among the first applications to exploit the microRNA regulatory pathway, provides the basis for a promising new therapy for the treatment of hemophilia B.
引用
收藏
页码:4144 / 4152
页数:9
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