دورية أكاديمية
أعرض في EDS

Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases.

التفاصيل البيبلوغرافية
العنوان: Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases.
المؤلفون: Esposito F; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Dell'Aquila F; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Medical Genetics, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy., Rhiel M; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Freiburg, Germany., Auricchio S; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Chmielewski KO; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Freiburg, Germany; PhD Program, Faculty of Biology, University of Freiburg, Freiburg, Germany., Andrieux G; Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany., Ferla R; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Horrach PS; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Padmanabhan A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Di Cunto R; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Notaro S; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Santeularia ML; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Boerries M; Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany., Dell'Anno M; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Nusco E; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Padula A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Nutarelli S; Department of Life Science and Public Health, Catholic University of the Sacred Heart, Rome, Italy., Cornu TI; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany., Sorrentino NC; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy., Piccolo P; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Trapani I; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Medical Genetics, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy., Cathomen T; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany., Auricchio A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Gene Therapy Joint lab, Dept. of Advanced Biomedical Sciences and Dept. of Translational Medicine, University of Naples 'Federico II', Naples, Italy. Electronic address: auricchio@tigem.it.
المصدر: Cell reports. Medicine [Cell Rep Med] 2024 Jul 16; Vol. 5 (7), pp. 101619. Date of Electronic Publication: 2024 Jun 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 101766894 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-3791 (Electronic) Linking ISSN: 26663791 NLM ISO Abbreviation: Cell Rep Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Cambridge, MA] : Cell Press, [2020]-
مواضيع طبية MeSH: Dependovirus*/genetics , Liver*/metabolism , Liver*/pathology , Disease Models, Animal* , Genetic Vectors*/genetics, Animals ; Mice ; Hepatocytes/metabolism ; Humans ; Virus Integration/genetics ; CRISPR-Cas Systems/genetics ; Transgenes ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/therapy ; Genetic Therapy/methods ; Mice, Inbred C57BL ; Albumins/genetics ; Albumins/metabolism
مستخلص: Liver-directed adeno-associated viral (AAV) vector-mediated homology-independent targeted integration (AAV-HITI) by CRISPR-Cas9 at the highly transcribed albumin locus is under investigation to provide sustained transgene expression following neonatal treatment. We show that targeting the 3' end of the albumin locus results in productive integration in about 15% of mouse hepatocytes achieving therapeutic levels of systemic proteins in two mouse models of inherited diseases. We demonstrate that full-length HITI donor DNA is preferentially integrated upon nuclease cleavage and that, despite partial AAV genome integrations in the target locus, no gross chromosomal rearrangements or insertions/deletions at off-target sites are found. In line with this, no evidence of hepatocellular carcinoma is observed within the 1-year follow-up. Finally, AAV-HITI is effective at vector doses considered safe if directly translated to humans providing therapeutic efficacy in the adult liver in addition to newborn. Overall, our data support the development of this liver-directed AAV-based knockin strategy.
Competing Interests: Declaration of interests F.E., F.D.A., R.F., M.L.S., and A.A. are listed as inventors on the patent WO2023213831 “Homology independent targeted integration for gene editing” related to this work. A.A. is founder, shareholder, and consultant of InnovaVector s.r.l. and of AAVantgarde Bio s.r.l. R.F. is currently an employee of AAVantgarde Bio s.r.l. T.C., M.B., and G.A. are listed as inventors of CAST-Seq (EP3856928B1).
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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فهرسة مساهمة: Keywords: AAV; CAST-Seq; CRISPR-Cas9; HITI; genome editing; hemophilia A; homology-independent targeted integration; inherited diseases; in vivo; liver; mucopolysaccharidosis type VI; persistent transgene expression
المشرفين على المادة: 0 (Albumins)
تواريخ الأحداث: Date Created: 20240619 Date Completed: 20240717 Latest Revision: 20240803
رمز التحديث: 20240803
مُعرف محوري في PubMed: PMC11293346
DOI: 10.1016/j.xcrm.2024.101619
PMID: 38897206
قاعدة البيانات: MEDLINE
الوصف
تدمد:2666-3791
DOI:10.1016/j.xcrm.2024.101619