期刊
BLOOD
卷 123, 期 20, 页码 3195-3199出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-10-534032
关键词
-
类别
资金
- European Union [222878]
- Bayer-Schering
- Fonds Wetenschappelijk Onderzoek
- European Hematology Association
- Association francaise contre les myopathies
- Geconcerteerde Onderzoeks Actie (GOA: EPIGEN)
- Willy Gepts Fonds
- Strategic Research Programme-Grower Grant (SRP: GeneFIX)
- Industrieel Onderzoeksfonds-Groups of Expertise in Applied Research (IOF GEAR: GeneCure)
- Industrieel Onderzoeksfonds-Proof of Concept grant (IOF PoC)
The development of the next-generation gene therapy vectors for hemophilia requires using lower and thus potentially safer vector doses and augmenting their therapeutic efficacy. We have identified hepatocyte-specific transcriptional cis-regulatory modules (CRMs) by using a computational strategy that increased factor IX (FIX) levels 11- to 15-fold. Vector efficacy could be enhanced by combining these hepatocyte-specific CRMs with a synthetic codon-optimized hyperfunctional FIX-R338L Padua transgene. This Padua mutation boosted FIX activity up to sevenfold, with no apparent increase in thrombotic risk. We then validated this combination approach using self-complementary adenoassociated virus serotype 9 (scAAV9) vectors in hemophilia B mice. This resulted in sustained supraphysiologic FIX activity (400%), correction of the bleeding diathesis at clinically relevant, low vector doses (5 x 10(10) vector genomes [vg]/kg) that are considered safe in patients undergoing gene therapy. Moreover, immune tolerance could be induced that precluded induction of inhibitory antibodies to FIX upon immunization with recombinant FIX protein.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据