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In Vivo Hematopoietic Stem Cell Gene Therapy for SARS-CoV2 Infection Using a Decoy Receptor.
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, André.
  • Wang H; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Li C; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Obadan AO; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Frizzell H; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Hsiang TY; Department of Immunology, University of Washington, Seattle, Washington, USA.
  • Gil S; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Germond A; Washington National Primate Research Center, Seattle, Washington, USA.
  • Fountain C; Washington National Primate Research Center, Seattle, Washington, USA.
  • Baldessari A; Washington National Primate Research Center, Seattle, Washington, USA.
  • Roffler S; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • Kiem HP; Stem and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • Fuller DH; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Lieber A; Washington National Primate Research Center, Seattle, Washington, USA.
Hum Gene Ther ; 33(7-8): 389-403, 2022 04.
Article in English | MEDLINE | ID: covidwho-1806227
ABSTRACT
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 ß-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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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / COVID-19 Type of study: Prognostic study Topics: Long Covid / Vaccines / Variants Limits: Animals Language: English Journal: Hum Gene Ther Journal subject: Genetics, Medical / Therapeutics Year: 2022 Document Type: Article Affiliation country: Hum.2021.295

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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / COVID-19 Type of study: Prognostic study Topics: Long Covid / Vaccines / Variants Limits: Animals Language: English Journal: Hum Gene Ther Journal subject: Genetics, Medical / Therapeutics Year: 2022 Document Type: Article Affiliation country: Hum.2021.295