First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.
First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.
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DOI：
10.1016/j.ymthe.2022.10.010
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发表时间：
2022-12-07
影响因子：
12.4
通讯作者：
Muenzer, Joseph
中科院分区：
文献类型：
--
作者：
Harmatz, Paul;Prada, Carlos E.;Burton, Barbara K.;Lau, Heather;Kessler, Craig M.;Cao, Liching;Falaleeva, Marina;Villegas, Andres G.;Zeitler, Jennifer;Meyer, Kathleen;Miller, Weston;Foo, Cheryl Wong Po;Vaidya, Sagar;Swenson, Wendy;Shiue, Lisa H.;Rouy, Didier;Muenzer, Joseph
基于锌指核酸酶（ZFN）的体内基因组编辑是一种新的治疗方法，可以通过单次静脉给药提供终身蛋白质替代。从2017年11月开始，并行进行了三项首次人体开放标签上升单剂量1/2期研究，主要是为了评估ZFN体内编辑治疗粘多糖病I (MPS I) （n = 3）、MPS II （n = 9）和血友病B （n = 1）的安全性和耐受性。治疗耐受性良好，无严重的治疗相关不良事件。在1e13 vg/kg剂量下，通过MPS II （n = 2）和MPS I （n = 1）受试者肝脏中的白蛋白转基因融合转录物检测基因组编辑的证据。MPS I患者的白细胞伊杜糖醛酸酶活性也有短暂的升高，降至较低的正常范围。在5e13 vg/kg剂量下，一名MPS II受试者血浆中伊杜醛酸-2-硫酸酯酶短暂升高，接近正常水平，一名MPS I受试者白细胞伊杜醛酸酶活性接近中等正常水平，没有基因组编辑的证据。血友病B组患者不能减少因子IX浓缩物的使用；基因组编辑无法评估。总体而言，ZFN体内编辑疗法具有良好的安全性，有证据表明在肝脏中进行了靶向基因组编辑，但在血液中没有长期的酶表达。在这些首次人体研究中，ZFN在体内编辑具有良好的安全性，有证据表明，对于MPS I、MPS II和血友病B患者，在高达5e13 vg/kg的剂量下，ZFN在体内编辑具有靶向基因组编辑，但没有长期持续的酶表达。
Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood. In these first-in-human studies, ZFN in vivo editing had a favorable safety profile with evidence of targeted genome editing, but no long-term sustained enzyme expression, for subjects with MPS I, MPS II, and hemophilia B at doses up to 5e13 vg/kg.
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影响因子：
19.7
作者：
DELAND, FH;NORTH, WA
通讯作者：
NORTH, WA
影响因子：
3.8
作者：
Bell, Peter;Wang, Lili;Wilson, James M.
通讯作者：
Wilson, James M.
影响因子：
4.2
作者：
Lampe, Christina;Bosserhoff, Ann-Kathrin;Mendelsohn, Nancy J.
通讯作者：
Mendelsohn, Nancy J.
DOI：
10.1016/j.ymthe.2018.03.002
发表时间：
2018-04-04
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Laoharawee K;DeKelver RC;Podetz-Pedersen KM;Rohde M;Sproul S;Nguyen HO;Nguyen T;St Martin SJ;Ou L;Tom S;Radeke R;Meyer KE;Holmes MC;Whitley CB;Wechsler T;McIvor RS
通讯作者：
McIvor RS
影响因子：
3.6
作者：
Fraldi A;Serafini M;Sorrentino NC;Gentner B;Aiuti A;Bernardo ME
通讯作者：
Bernardo ME