دورية أكاديمية
T-cell specific in vivo gene delivery with DART-AAVs targeted to CD8.
| العنوان: | T-cell specific in vivo gene delivery with DART-AAVs targeted to CD8. |
|---|---|
| المؤلفون: | Demircan MB; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Zinser LJ; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Michels A; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Guaza-Lasheras M; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., John F; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt, Germany., Gorol JM; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt, Germany; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt, Germany., Theuerkauf SA; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Günther DM; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany; Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society, 60528 Frankfurt, Germany., Grimm D; Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, BioQuant, 69120 Heidelberg, Germany., Greten FR; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt, Germany; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt, Germany., Chlanda P; Schaller Research Groups, Department of Infectious Diseases/Virology, Medical Faculty, Heidelberg University, BioQuant, 69120 Heidelberg, Germany., Thalheimer FB; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany; HZG Hematology, Cell and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Buchholz CJ; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt, Germany. Electronic address: christian.buchholz@pei.de. |
| المصدر: | Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Aug 08. Date of Electronic Publication: 2024 Aug 08. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2017- : Cambridge, MA : Cell Press Original Publication: San Diego, CA : Academic Press, 2000- |
| مستخلص: | One of the biggest challenges for in vivo gene therapy are vectors mediating highly selective gene transfer into a defined population of therapy-relevant cells. Here we present DARPin-targeted AAVs (DART-AAVs) displaying DARPins specific for human and murine CD8. Insertion of DARPins into the GH2/GH3 loop of the capsid protein 1 (VP1) of AAV2 and AAV6 resulted in high selectivity for CD8-positive T cells with unimpaired gene delivery activity. Remarkably, the capsid core structure was unaltered with protruding DARPins detectable. In complex primary cell mixtures, including donor blood or systemic injections into mice, the CD8-targeted AAVs were by far superior to unmodified AAV2 and AAV6 in terms of selectivity, target cell viability, and gene transfer rates. In vivo, up to 80% of activated CD8+ T cells were hit upon a single vector injection into conditioned humanized or immunocompetent mice. While gene transfer rates decreased significantly under non-activated conditions, genomic modification selectively in CD8+ T cells was still detectable upon Cre delivery into indicator mice. In both mouse models, selectivity for CD8+ T cells was close to absolute with exceptional detargeting from liver. The CD8-AAVs described here expand strategies for immunological research and in vivo gene therapy options. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: AAV capsid engineering; CD8 targeting; CD8-AAV; DART-AAVs; T cell activation; T cell targeting; gene therapy; in vivo delivery; in vivo gene therapy; receptor targeting; targeted AAV; targeted gene therapy; viral vectors |
| تواريخ الأحداث: | Date Created: 20240808 Latest Revision: 20240824 |
| رمز التحديث: | 20240826 |
| DOI: | 10.1016/j.ymthe.2024.08.002 |
| PMID: | 39113357 |
| قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!