Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B

被引：82

作者：

Arruda, Valder R. ^{[1
,2
]}

Stedman, Hansell H. ^{[2
]}

Haurigot, Virginia ^{[1
,3
]}

Buchlis, George ^{[2
]}

Baila, Stefano ^{[1
]}

Favaro, Patricia ^{[1
]}

Chen, Yifeng ^{[1
,3
]}

Franck, Helen G. ^{[4
]}

Zhou, Shangzhen ^{[1
]}

Wright, J. Fraser ^{[1
,2
]}

Couto, Linda B. ^{[1
]}

Jiang, Haiyan ^{[5
]}

Pierce, Glenn F. ^{[5
]}

Bellinger, Dwight A. ^{[4
]}

Mingozzi, Federico ^{[1
]}

Nichols, Timothy C. ^{[4
]}

High, Katherine A. ^{[1
,2
,3
]}

机构：

[1] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Philadelphia, PA 19104 USA

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

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

[5] Biogen Idec Inc, Waltham, MA USA

来源：

BLOOD | 2010年 / 115卷 / 23期

基金：

美国国家卫生研究院;

关键词：

LONG-TERM CORRECTION; LEBERS CONGENITAL AMAUROSIS; DUCHENNE MUSCULAR-DYSTROPHY; MEDIATED GENE-TRANSFER; COAGULATION FACTOR-IX; IMMUNE-RESPONSES; VASCULAR DELIVERY; CELL RESPONSES; CLINICAL-TRIAL; NULL MUTATION;

D O I：

10.1182/blood-2009-12-261156

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Muscle represents an important tissue target for adeno-associated viral (AAV) vector-mediated gene transfer of the factor IX (FIX) gene in hemophilia B (HB) subjects with advanced liver disease. Previous studies of direct intramuscular administration of an AAV-FIX vector in humans showed limited efficacy. Here we adapted an intravascular delivery system of AAV vectors encoding the FIX transgene to skeletal muscle of HB dogs. The procedure, performed under transient immunosuppression (IS), resulted in widespread transduction of muscle and sustained, dose-dependent therapeutic levels of canine FIX transgene up to 10-fold higher than those obtained by intramuscular delivery. Correction of bleeding time correlated clinically with a dramatic reduction of spontaneous bleeding episodes. None of the dogs (n = 14) receiving the AAV vector under transient IS developed inhibitory antibodies to canine FIX; transient inhibitor was detected after vector delivery without IS. The use of AAV sero-types with high tropism for muscle and low susceptibility to anti-AAV2 antibodies allowed for efficient vector administration in naive dogs and in the presence of low- but not high-titer anti-AAV2 antibodies. Collectively, these results demonstrate the feasibility of this approach for treatment of HB and highlight the importance of IS to prevent immune responses to the FIX transgene product. (Blood. 2010;115(23):4678-4688)

引用

页码：4678 / 4688

页数：11

共 51 条

[51] Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression
Wang, Zejing
Kuhr, Christian S.
Allen, James M.
Blankinship, Michael
Gregorevic, Paul
Chamberlain, Jeffrey S.
Tapscott, Stephen J.
Storb, Rainer
[J]. MOLECULAR THERAPY, 2007, 15 (06) : 1160 - 1166

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