Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

被引：578

作者：

George, L. A. ^{[1
,2
,3
]}

Sullivan, S. K. ^{[6
]}

Giermasz, A. ^{[9
]}

Rasko, J. E. J. ^{[11
,12
,13
]}

Samelson-Jones, B. J. ^{[1
,2
,3
]}

Ducore, J. ^{[10
]}

Cuker, A. ^{[4
]}

Sullivan, L. M. ^{[7
]}

Majumdar, S. ^{[8
]}

Teitel, J. ^{[14
,15
]}

McGuinn, C. E. ^{[16
]}

Ragni, M. V. ^{[17
]}

Luk, A. Y. ^{[5
]}

Hui, D. ^{[5
]}

Wright, J. F. ^{[5
]}

Chen, Y. ^{[5
]}

Liu, Y. ^{[5
]}

Wachtel, K. ^{[5
]}

Winters, A. ^{[1
,2
]}

Tiefenbacher, S. ^{[18
]}

Arruda, V. R. ^{[1
,2
,3
]}

van der Loo, J. C. M. ^{[2
]}

Zelenaia, O. ^{[2
]}

Takefman, D. ^{[5
]}

Carr, M. E. ^{[5
]}

Couto, L. B. ^{[5
]}

Anguela, X. M. ^{[5
]}

High, K. A. ^{[5
]}

机构：

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

[2] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

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

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

[5] Spark Therapeut, Philadelphia, PA USA

[6] Mississippi Ctr Adv Med, Dept Pediat, Madison, MS USA

[7] Univ Mississippi, Med Sch, Dept Pathol, Jackson, MS USA

[8] Univ Mississippi, Med Sch, Dept Pediat, Jackson, MS USA

[9] Univ Calif Davis, Sch Med, Dept Med, Sacramento, CA 95817 USA

[10] Univ Calif Davis, Sch Med, Dept Pediat, Sacramento, CA 95817 USA

[11] Univ Sydney, Sydney Med Sch, Dept Med, Camperdown, NSW, Australia

[12] Univ Sydney, Centenary Inst, Gene & Stem Cell Therapy Program, Camperdown, NSW, Australia

[13] Royal Prince Alfred Hosp, Cell & Mol Therapies, Camperdown, NSW, Australia

[14] Univ Toronto, Fac Med, Dept Med, Toronto, ON, Canada

[15] St Michaels Hosp, Toronto, ON, Canada

[16] Weill Cornell Med Coll, Dept Pediat, New York, NY USA

[17] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA

[18] Lab Corp Amer Holdings, Colorado Coagulat, Englewood, CO USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2017年 / 377卷 / 23期

关键词：

AAV VECTOR; IDENTIFICATION; TRANSDUCTION; EXPRESSION; EFFICIENT; EFFICACY; SAFETY; LIVER; PADUA; TRIAL;

D O I：

10.1056/NEJMoa1708538

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5x10(11) vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. RESULTS No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (+/- SD) steady-state factor IX coagulant activity of 33.7 +/- 18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P = 0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P = 0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. CONCLUSIONS We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use.

引用

页码：2215 / 2227

页数：13

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