Adenovirus-Associated Virus Vector-Mediated Gene Transfer in Hemophilia B

被引：1423

作者：

Nathwani, Amit C. ^{[1
,2
,3
,5
]}

Tuddenham, Edward G. D. ^{[2
,3
]}

Rangarajan, Savita ^{[7
]}

Rosales, Cecilia ^{[1
,5
]}

McIntosh, Jenny ^{[1
,5
]}

Linch, David C. ^{[1
]}

Chowdary, Pratima ^{[2
,3
]}

Riddell, Anne ^{[2
,3
]}

Pie, Arnulfo Jaquilmac ^{[2
,3
]}

Harrington, Chris ^{[2
,3
]}

O'Beirne, James ^{[4
]}

Smith, Keith ^{[5
]}

Pasi, John ^{[6
]}

Glader, Bertil ^{[8
]}

Rustagi, Pradip ^{[8
]}

Ng, Catherine Y. C. ^{[9
]}

Kay, Mark A. ^{[8
]}

Zhou, Junfang ^{[9
]}

Spence, Yunyu ^{[9
]}

Morton, Christopher L. ^{[9
]}

Allay, James ^{[12
]}

Coleman, John ^{[12
]}

Sleep, Susan ^{[12
]}

Cunningham, John M. ^{[13
]}

Srivastava, Deokumar ^{[10
]}

Basner-Tschakarjan, Etiena ^{[14
]}

Mingozzi, Federico ^{[14
]}

High, Katherine A. ^{[14
,15
]}

Gray, John T. ^{[11
]}

Reiss, Ulrike M. ^{[11
]}

Nienhuis, Arthur W. ^{[11
]}

Davidoff, Andrew M. ^{[9
]}

机构：

[1] UCL, Inst Canc, Dept Haematol, London WC1E 6BT, England

[2] Royal Free Natl Hlth Serv NHS Trust, Katharine Dormandy Haemophilia Ctr, London, England

[3] Royal Free Natl Hlth Serv NHS Trust, Thrombosis Unit, London, England

[4] Royal Free Natl Hlth Serv NHS Trust, Liver Unit, London, England

[5] NHS Blood & Transplant, London, England

[6] Barts & London Queen Marys Sch Med & Dent, Ctr Haematol, London, England

[7] Basingstoke & N Hampshire NHS Fdn Trust, Basingstoke, Hants, England

[8] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA

[9] St Jude Childrens Hosp, Dept Surg, Memphis, TN 38105 USA

[10] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA

[11] St Jude Childrens Hosp, Dept Hematol, Memphis, TN 38105 USA

[12] Childrens GMP, Memphis, TN USA

[13] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA

[14] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

[15] Howard Hughes Med Inst, Chevy Chase, MD USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2011年 / 365卷 / 25期

基金：

英国医学研究理事会;

关键词：

ADENOASSOCIATED VIRAL VECTOR; HUMAN-FACTOR IX; CLINICAL-TRIAL; EFFICIENT TRANSDUCTION; IMMUNE-RESPONSE; HUMAN FIX; LIVER; EXPRESSION; THERAPY; EXERCISE;

D O I：

10.1056/NEJMoa1108046

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.)

引用

页码：2357 / 2365

页数：9

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