The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy

被引：87

作者：

Finn, Jonathan D.

Nichols, Timothy C. ^{[2
]}

Svoronos, Nikolaos

Merricks, Elizabeth P. ^{[2
]}

Bellenger, Dwight A. ^{[2
]}

Zhou, Shangshen

Simioni, Paolo ^{[3
]}

High, Katherine A. ^{[4
,5
]}

Arruda, Valder R. ^{[1
,5
]}

机构：

[1] Childrens Hosp Philadelphia, Colket Translat Res Ctr 5056, Philadelphia, PA 19104 USA

[2] Univ N Carolina, Chapel Hill, NC USA

[3] Univ Padua, Padua, Italy

[4] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

BLOOD | 2012年 / 120卷 / 23期

基金：

美国国家卫生研究院;

关键词：

FACTOR-IX EXPRESSION; LONG-TERM CORRECTION; SKELETAL-MUSCLE; DELIVERY; VECTORS; IMPROVE; MODELS; LIVER;

D O I：

10.1182/blood-2012-06-440123

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Studies on gene therapy for hemophilia B (HB) using adeno-associated viral (AAV) vectors showed that the safety of a given strategy is directly related to the vector dose. To overcome this limitation, we sought to test the efficacy and the risk of immunogenicity of a novel factor IX (FIX) R338L associated with similar to 8-fold increased specific activity. Muscle-directed expression of canine FIX-R338L by AAV vectors was carried out in HB dogs. Therapeutic levels of circulating canine FIX activity (3.5%-8%) showed 8- to 9-fold increased specific activity, similar to humans with FIX-R338L. Phenotypic improvement was documented by the lack of bleeding episodes for a cumulative 5-year observation. No antibody formation and T-cell responses to FIX-R338L were observed, even on challenges with FIX wild-type protein. Moreover, no adverse vascular thrombotic complications were noted. Thus, FIX-R338L provides an attractive strategy to safely enhance the efficacy of gene therapy for HB. (Blood. 2012;120(23):4521-4523)

引用

收藏

页码：4521 / 4523

页数：3

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