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

被引：1397

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

共 50 条

[1] Adenovirus vector-mediated gene transfer into stem cells
Kawabata, Kenji
Sakurai, Funlinori
Koizumi, Naoya
Hayakawa, Takao
Mizuguchi, Hiroyuki
[J]. MOLECULAR PHARMACEUTICS, 2006, 3 (02) : 95 - 103
[2] Viral vector-mediated gene therapy for hemophilia B
Eisensmith, RC
Woo, SLC
[J]. THROMBOSIS AND HAEMOSTASIS, 1997, 78 (01) : 24 - 30
[3] Laser photocoagulation enhances gene transfer mediated by Adenovirus-associated virus vector in mouse retinal tissue.
Park, Tae Kwann
Lee, Si Hyung
Lee, Tae Gon
Lee, Heuiran
[J]. HUMAN GENE THERAPY, 2012, 23 (10) : A82 - A82
[4] VIRUS VECTOR-MEDIATED GENE-TRANSFER
LEVINE, AJ
[J]. MICROBIOLOGICAL SCIENCES, 1987, 4 (08): : 245 - 250
[5] Adenovirus vector-mediated gene transfer to regional lymph nodes
Labow, D
Lee, S
Ginsberg, RJ
Crystal, RG
Korst, RJ
[J]. HUMAN GENE THERAPY, 2000, 11 (05) : 759 - 769
[6] Adeno-Associated Virus —Mediated Gene Transfer for Hemophilia B
Katherine A. High
[J]. International Journal of Hematology, 2002, 76 : 310 - 318
[7] Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract
F Kurosaki
R Uchibori
N Mato
Y Sehara
Y Saga
M Urabe
H Mizukami
Y Sugiyama
A Kume
[J]. Gene Therapy, 2017, 24 : 290 - 297
[8] Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract
Kurosaki, F.
Uchibori, R.
Mato, N.
Sehara, Y.
Saga, Y.
Urabe, M.
Mizukami, H.
Sugiyama, Y.
Kume, A.
[J]. GENE THERAPY, 2017, 24 (05) : 290 - 297
[9] Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B
Nathwani, Amit C.
Tuddenham, Edward G. D.
Rangarajan, Savita
Rosales, Cecilia
McIntosh, Jenny H.
Linch, David C.
Chowdary, Pratima
Griffioen, Anja
Riddell, Anne
Pie, Jun
Harrington, Chris
O'Beirne, James
Smith, Keith
Pasi, John
Glader, Bertil
Rustagi, Pradip
Ng, Catherine
Kay, Mark
Zhou, Junfang
Spence, Yunyu
Morton, Christopher
Allay, James
Coleman, John
Sleep, Susan
Cunningham, John M.
Basner-Tschakarjan, Etiena
Mingozzi, Federico
High, Katherine A.
Gray, John T.
Reiss, Ulrike M.
Nienhuis, Arthur W.
Davidoff, Andrew
[J]. BLOOD, 2011, 118 (21) : 4 - 5
[10] ADENOVIRUS VECTOR-MEDIATED GENE-TRANSFER INTO ADULT-RAT CHOROID
BLASI, MA
ROTA, R
GIULIANO, M
CAPOGROSSI, M
PROCOPIO, A
BALESTRAZZI, E
[J]. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 1995, 36 (04) : S845 - S845

← 1 2 3 4 5 →