In Vivo Hematopoietic Stem Cell Gene Therapy for SARS-CoV2 Infection Using a Decoy Receptor.
In Vivo Hematopoietic Stem Cell Gene Therapy for SARS-CoV2 Infection Using a Decoy Receptor.
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DOI：
10.1089/hum.2021.295
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发表时间：
2022-04
影响因子：
4.2
通讯作者：
Lieber, Andre
中科院分区：
文献类型：
--
作者：
Wang, Hongjie;Li, Chang;Obadan, Adebimpe O.;Frizzell, Hannah;Hsiang, Tien-Ying;Gil, Sucheol;Germond, Audrey;Fountain, Connie;Baldessari, Audrey;Roffler, Steve;Kiem, Hans-Peter;Fuller, Deborah H.;Lieber, Andre
虽然SARS-CoV2疫苗取得了前所未有的成功，但新变种的不断出现和调整疫苗的必要性证明了开发替代预防和治疗方法的合理性。使用分泌型CoV2诱骗受体蛋白(sACE2-Ig)的造血干细胞(HSC)基因治疗将涉及一次性干预，从而对呼吸道感染、病毒血症和肺外症状产生长期保护。我们最近开发了一种技术简单且可移植的体内造血HSC转导方法，包括从骨髓动员HSC进入外周血流，并静脉注射整合的辅助依赖型腺病毒(HDAd5/35++)载体系统。考虑到红细胞的丰度，在本研究中，我们利用强大的β-珠蛋白转录调控元件将sACE2-Ig的表达导向红系细胞。我们用HDAd-sACE2-Ig载体对CD46转基因小鼠进行了体内HSC转导。经体内筛选后，血清sACE2-Ig水平达到500~1300 ng/mL。在22周时，我们使用这些小鼠的转基因HSCs来替代人类ACE2转基因小鼠的造血系统，从而创建了一个容易感染SARS-CoV2的模型。当用致死剂量的CoV2(WA-1)攻击时，试验小鼠红系细胞表达的sACE2-Ig可减少感染后遗症。经治疗的小鼠体重显著减少，病毒血症较少，细胞因子产生减少，肺部病理改变减少。这项研究的第二个目标是评估体内HSC转导的安全性和恒河猴体内sACE2-Ig的长期表达。在适当的细胞因子预防下，静脉注射HDAd-sACE2-Ig到动员的动物体内是耐受性良好的。体内转导的HSCs优先定位于脾内并存活。红系细胞表达的sACE2-Ig不影响红细胞生成和红细胞功能。虽然这些初步研究是有希望的，但该方法的抗病毒效果必须得到改善，例如，通过使用具有增强的中和能力和/或多种抗病毒效应蛋白表达的诱骗受体。
While SARS-CoV2 vaccines have shown an unprecedented success, the ongoing emergence of new variants and necessity to adjust vaccines justify the development of alternative prophylaxis and therapy approaches. Hematopoietic stem cell (HSC) gene therapy using a secreted CoV2 decoy receptor protein (sACE2-Ig) would involve a one-time intervention resulting in long-term protection against airway infection, viremia, and extrapulmonary symptoms. We recently developed a technically simple and portable in vivo hematopoietic HSC transduction approach that involves HSC mobilization from the bone marrow into the peripheral blood stream and the intravenous injection of an integrating, helper-dependent adenovirus (HDAd5/35++) vector system. Considering the abundance of erythrocytes, in this study, we directed sACE2-Ig expression to erythroid cells using strong β-globin transcriptional regulatory elements. We performed in vivo HSC transduction of CD46-transgenic mice with an HDAd-sACE2-Ig vector. Serum sACE2-Ig levels reached 500–1,300 ng/mL after in vivo selection. At 22 weeks, we used genetically modified HSCs from these mice to substitute the hematopoietic system in human ACE2-transgenic mice, thus creating a model that is susceptible to SARS-CoV2 infection. Upon challenge with a lethal dose of CoV2 (WA-1), sACE2-Ig expressed from erythroid cells of test mice diminishes infection sequelae. Treated mice lost significantly less weight, had less viremia, and displayed reduced cytokine production and lung pathology. The second objective of this study was to assess the safety of in vivo HSC transduction and long-term sACE2-Ig expression in a rhesus macaque. With appropriate cytokine prophylaxis, intravenous injection of HDAd-sACE2-Ig into the mobilized animal was well tolerated. In vivo transduced HSCs preferentially localized to and survived in the spleen. sACE2-Ig expressed from erythroid cells did not affect erythropoiesis and the function of erythrocytes. While these pilot studies are promising, the antiviral efficacy of the approach has to be improved, for example, by using of decoy receptors with enhanced neutralizing capacity and/or expression of multiple antiviral effector proteins.
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DOI：
10.1016/j.omtm.2021.12.003
发表时间：
2022-03-10
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Li C;Wang H;Gil S;Germond A;Fountain C;Baldessari A;Kim J;Liu Z;Georgakopoulou A;Radtke S;Raskó T;Pande A;Chiang C;Chin E;Yannaki E;Izsvák Z;Papayannopoulou T;Kiem HP;Lieber A
通讯作者：
Lieber A
影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
影响因子：
64.8
作者：
Gardner, Matthew R.;Kattenhorn, Lisa M.;Kondur, Hema R.;von Schaewen, Markus;Dorfman, Tatyana;Chiang, Jessica J.;Haworth, Kevin G.;Decker, Julie M.;Alpert, Michael D.;Bailey, Charles C.;Neale, Ernest S., Jr.;Fellinger, Christoph H.;Joshi, Vinita R.;Fuchs, Sebastian P.;Martinez-Navio, Jose M.;Quinlan, Brian D.;Yao, Annie Y.;Mouquet, Hugo;Gorman, Jason;Zhang, Baoshan;Poignard, Pascal;Nussenzweig, Michel C.;Burton, Dennis R.;Kwong, Peter D.;Piatak, Michael, Jr.;Lifson, Jeffrey D.;Gao, Guangping;Desrosiers, Ronald C.;Evans, David T.;Hahn, Beatrice H.;Ploss, Alexander;Cannon, Paula M.;Seaman, Michael S.;Farzan, Michael
通讯作者：
Farzan, Michael
影响因子：
5.4
作者：
Fetzer, Ina;Gardner, Matthew R.;Farzan, Michael
通讯作者：
Farzan, Michael
影响因子：
7.5
作者：
Li, Chang;Goncalves, Kevin A.;Lieber, Andre
通讯作者：
Lieber, Andre