JOM KITA KE POLITEKNIK

In vivo prime editing of a metabolic liver disease in mice (Record no. 953)

MARC details
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Personal name Böck, Desirée
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9 (RLIN) 2742
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Title In vivo prime editing of a metabolic liver disease in mice
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Date of publication, distribution, etc. 2022-03-16.
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General note /pmc/articles/PMC7614134/
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General note /pubmed/35294257
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Summary, etc. Prime editing is a highly versatile CRISPR-based genome editing technology that works without DNA double-strand break formation. Despite rapid technological advances, in vivo application for the treatment of genetic diseases remains challenging. Here, we developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain (PE2(ΔRnH)) and an intein-split construct (PE2 p.1153) for adeno-associated virus (AAV)-mediated delivery into the liver. Editing efficiencies reached 15% at the Dnmt1 locus, and were further elevated to 58% by delivering unsplit PE2(ΔRnH) via human adenoviral vector 5 (AdV). To provide proof-of-concept for correcting a genetic liver disease, we next employed the AdV approach for repairing the disease-causing Pah(enu2) mutation in a mouse model of phenylketonuria (PKU) via prime editing. Average correction efficiencies of 11.1% (up to 17.4%) in neonates led to therapeutic reduction of blood phenylalanine (L-Phe), without inducing detectable off-target mutations or prolonged liver inflammation. Although the current in vivo prime editing approach for PKU has limitations for clinical application due to the requirement of high vector doses (7×10(14) vg/kg) and the induction of immune responses to the vector and the PE, further development of the technology may lead to curative therapies for PKU and other genetic liver diseases.
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Language note en
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Personal name Rothgangl, Tanja
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9 (RLIN) 2743
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Personal name Villiger, Lukas
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9 (RLIN) 2744
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Personal name Schmidheini, Lukas
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9 (RLIN) 2745
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Personal name Matsushita, Mai
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9 (RLIN) 2746
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Personal name Mathis, Nicolas
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9 (RLIN) 2747
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Personal name Ioannidi, Eleonora
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9 (RLIN) 2748
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Personal name Rimann, Nicole
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9 (RLIN) 2749
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Personal name Grisch-Chan, Hiu Man
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9 (RLIN) 2750
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Personal name Kreutzer, Susanne
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9 (RLIN) 2751
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Personal name Kontarakis, Zacharias
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9 (RLIN) 2752
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Personal name Kopf, Manfred
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9 (RLIN) 2753
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Personal name Thöny, Beat
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9 (RLIN) 2754
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Personal name Schwank, Gerald
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9 (RLIN) 2755
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Note Sci Transl Med
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Uniform Resource Identifier <a href="http://dx.doi.org/10.1126/scitranslmed.abl9238">http://dx.doi.org/10.1126/scitranslmed.abl9238</a>
Public note Connect to this object online.

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