AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

被引：120

作者：

Crudele, Julie M. ^{[1
]}

Finn, Jonathan D. ^{[1
]}

Siner, Joshua I. ^{[1
]}

Martin, Nicholas B. ^{[1
]}

Niemeyer, Glenn P. ^{[2
]}

Zhou, Shangzhen ^{[1
]}

Mingozzi, Federico ^{[1
]}

Lothrop, Clinton D., Jr. ^{[2
]}

Arruda, Valder R. ^{[1
,3
]}

机构：

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

[2] Univ Alabama Birmingham, Dept Biochem, Birmingham, AL USA

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

来源：

BLOOD | 2015年 / 125卷 / 10期

基金：

美国国家卫生研究院;

关键词：

LONG-TERM CORRECTION; FACTOR-IX; FACTOR-VIII; GENE-TRANSFER; IMMUNE TOLERANCE; NEUTRALIZING ANTIBODIES; SKELETAL-MUSCLE; IFN-GAMMA; T-CELLS; MUTATION;

D O I：

10.1182/blood-2014-07-588194

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 x 10(12) vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naive HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached similar to 200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB.

引用

页码：1553 / 1561

页数：9

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