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  Lentiviral and adeno-associated vectors efficiently transduce mouse T lymphocytes when targeted to murine CD8

Michels, A., Frank, A. M., Günther, D. M., Mataei, M., Börner, K., Grimm, D., et al. (2021). Lentiviral and adeno-associated vectors efficiently transduce mouse T lymphocytes when targeted to murine CD8. Mol Ther Methods Clin Dev, 23, 334-347. doi:10.1016/j.omtm.2021.09.014.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0009-D149-9 Version Permalink: https://hdl.handle.net/21.11116/0000-000C-7959-9
Genre: Journal Article

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Michels_2021_LentiviralAndAdeno-associated.pdf
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2021
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Copyright © 2021 The Author(s)
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https://www.sciencedirect.com/science/article/pii/S2329050121001522 (Publisher version)
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 Creators:
Michels, Alexander, Author
Frank, Annika M., Author
Günther, Dorothee M.1, 2, Author
Mataei, Mehryad, Author
Börner, Kathleen, Author
Grimm, Dirk, Author
Hartmann, Jessica, Author
Buchholz, Christian J., Author
Affiliations:
1Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Max Planck Society, Deutschordenstr. 46, 60528 Frankfurt, DE, ou_2074314              
2Fries Lab, Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Max Planck Society, Deutschordenstraße 46, 60528 Frankfurt, DE, ou_3381216              

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Free keywords: AAV capsid engineering Car cancer immunotherapy chimeric antigen receptor gene therapy splenocytes viral vectors D.G. is a co-founder, shareholder, and Chief Scientific Officer of AaviGen GmbH. All the other authors declare no competing interests.
 Abstract: Preclinical studies on gene delivery into mouse lymphocytes are often hampered by insufficient activity of lentiviral (LV) and adeno-associated vectors (AAVs) as well as missing tools for cell type selectivity when considering in vivo gene therapy. Here, we selected designed ankyrin repeat proteins (DARPins) binding to murine CD8. The top-performing DARPin was displayed as targeting ligand on both vector systems. When used on engineered measles virus (MV) glycoproteins, the resulting mCD8-LV transduced CD8+ mouse lymphocytes with near-absolute (>99%) selectivity. Despite its lower functional titer, mCD8-LV achieved 4-fold higher gene delivery to CD8+ cells than conventional VSV-LV when added to whole mouse blood. Addition of mCD8-LV encoding a chimeric antigen receptor (CAR) specific for mouse CD19 to splenocytes resulted in elimination of B lymphocytes and lymphoma cells. For display on AAV, the DARPin was inserted into the GH2-GH3 loop of the AAV2 capsid protein VP1, resulting in a DARPin-targeted AAV we termed DART-AAV. Stocks of mCD8-AAV contained similar genome copies as AAV2 but were >20-fold more active in gene delivery in mouse splenocytes, while exhibiting >99% specificity for CD8+ cells. These results suggest that receptor targeting can overcome blocks in transduction of mouse splenocytes.

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Language(s): eng - English
 Dates: 2021-10-012021-12-10
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.omtm.2021.09.014
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Title: Mol Ther Methods Clin Dev
Source Genre: Journal
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Publ. Info: Cell Press
Pages: - Volume / Issue: 23 Sequence Number: - Start / End Page: 334 - 347 Identifier: ISSN: 2329-0501