Report
Treatment of a metabolic liver disease by in vivo prime editing in mice
| العنوان: | Treatment of a metabolic liver disease by in vivo prime editing in mice |
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| المؤلفون: | Böck, Desirée, Rothgangl, Tanja, Villiger, Lukas, Schmidheini, Lukas, Mathis, Nicholas, Ioannidi, Eleonora, Kreutzer, Susanne, Kontarakis, Zacharias, Rimann, Nicole, Grisch-Chan, Hiu Man, Thöny, Beat, Schwank, Gerald |
| المصدر: | Böck, Desirée; Rothgangl, Tanja; Villiger, Lukas; Schmidheini, Lukas; Mathis, Nicholas; Ioannidi, Eleonora; Kreutzer, Susanne; Kontarakis, Zacharias; Rimann, Nicole; Grisch-Chan, Hiu Man; Thöny, Beat; Schwank, Gerald (2021). Treatment of a metabolic liver disease by in vivo prime editing in mice. bioRxiv 456632, Cold Spring Harbor Laboratory. |
| سنة النشر: | 2021 |
| المجموعة: | University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| مصطلحات موضوعية: | Institute of Pharmacology and Toxicology, 570 Life sciences, biology, 610 Medicine & health |
| الوصف: | Prime editing is a highly versatile CRISPR-based genome editing technology with the potential to correct the vast majority of pathogenic mutations (1). However, correction of a disease phenotype in vivo in somatic tissues has not been demonstrated thus far. Here, we establish proof-of-concept for in vivo prime editing and repair the metabolic liver disease phenylketonuria (PKU) in mice. We first developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain of the reverse transcriptase (PE2ΔRnH), and a linker- and NLS-optimized intein-split PE construct (PE2 p.1153) for delivery by adeno-associated virus (AAV) vectors. Systemic dual AAV-mediated delivery of this variant into the liver of neonatal mice enabled installation of a transversion mutation at the Dnmt1 locus with an average efficiency of 15%, and delivery of unsplit PE2ΔRnH using human adenoviral vector 5 (AdV5) further increased editing rates to 58%. PE2ΔRnH-encoding AdV5 was also used to correct the disease-causing mutation of the phenylalanine hydroxylase (Pah)enu2 allele in phenylketonuria (PKU) mice with an average efficiency of 8% (up to 17.3%), leading to therapeutic reduction of blood phenylalanine (L-Phe) levels. Our study demonstrates in vivo prime editing in the liver with high precision and editing rates sufficient to treat a number of metabolic liver diseases, emphasizing the potential of prime editing for future therapeutic applications. |
| نوع الوثيقة: | report |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2164-7844 |
| Relation: | https://www.zora.uzh.ch/id/eprint/214146/1/2021.08.17.456632v1.full.pdf; urn:issn:2164-7844 |
| DOI: | 10.5167/uzh-214146 |
| DOI: | 10.1101/2021.08.17.456632 |
| الاتاحة: | https://www.zora.uzh.ch/id/eprint/214146/ https://www.zora.uzh.ch/id/eprint/214146/1/2021.08.17.456632v1.full.pdf https://doi.org/10.5167/uzh-214146 https://doi.org/10.1101/2021.08.17.456632 |
| Rights: | info:eu-repo/semantics/openAccess ; Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ; http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| رقم الانضمام: | edsbas.4282725B |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 21647844 |
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| DOI: | 10.5167/uzh-214146 |