Modifying immune responses to adeno-associated virus vectors by capsid engineering.

Autor:	Bentler M; Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany., Hardet R; University of Rouen, INSERM, U1234, Pathophysiology Autoimmunity and Immunotherapy (PANTHER), Normandie University, 76000 Rouen, France., Ertelt M; Institute for Drug Discovery, University of Leipzig Medical Center, 04103 Leipzig, Germany.; Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Dresden/Leipzig, Germany., Rudolf D; Laboratory for Vector Based Immunotherapy, Fraunhofer Institute for Cell Therapy and Immunology (IZI), 04103 Leipzig, Germany., Kaniowska D; Laboratory for Vector Based Immunotherapy, Fraunhofer Institute for Cell Therapy and Immunology (IZI), 04103 Leipzig, Germany.; Department of Medicine II, University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, 04103 Leipzig, Germany., Schneider A; Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany., Vondran FWR; ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, 30625 Hannover, Germany.; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany., Schoeder CT; Institute for Drug Discovery, University of Leipzig Medical Center, 04103 Leipzig, Germany., Delphin M; CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France., Lucifora J; CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France., Ott M; Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany., Hacker UT; Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.; Laboratory for Vector Based Immunotherapy, Fraunhofer Institute for Cell Therapy and Immunology (IZI), 04103 Leipzig, Germany.; Department of Medicine II, University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, 04103 Leipzig, Germany., Adriouch S; University of Rouen, INSERM, U1234, Pathophysiology Autoimmunity and Immunotherapy (PANTHER), Normandie University, 76000 Rouen, France., Büning H; Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2023 Aug 22; Vol. 30, pp. 576-592. Date of Electronic Publication: 2023 Aug 22 (Print Publication: 2023).
DOI:	10.1016/j.omtm.2023.08.015
Abstrakt:	De novo immune responses are considered major challenges in gene therapy. With the aim to lower innate immune responses directly in cells targeted by adeno-associated virus (AAV) vectors, we equipped the vector capsid with a peptide known to interfere with Toll-like receptor signaling. Specifically, we genetically inserted in each of the 60 AAV2 capsid subunits the myeloid differentiation primary response 88 (MyD88)-derived peptide RDVLPGT, known to block MyD88 dimerization. Inserting the peptide neither interfered with capsid assembly nor with vector production yield. The novel capsid variant, AAV2.MB453, showed superior transduction efficiency compared to AAV2 in human monocyte-derived dendritic cells and in primary human hepatocyte cultures. In line with our hypothesis, AAV2.MB453 and AAV2 differed regarding innate immune response activation in primary human cells, particularly for type I interferons. Furthermore, mice treated with AAV2.MB453 showed significantly reduced CD8 + T cell responses against the transgene product for different administration routes and against the capsid following intramuscular administration. Moreover, humoral responses against the capsid were mitigated as indicated by delayed IgG2a antibody formation and an increased NAb50. To conclude, insertion of the MyD88-derived peptide into the AAV2 capsid improved early steps of host-vector interaction and reduced innate and adaptive immune responses. Competing Interests: H.B. is an inventor on patent applications focusing on AAV capsid engineering. The remaining authors declare no conflict of interests. (© 2023 The Authors.)
Databáze:	MEDLINE
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