Prime editing for functional repair in patient-derived disease models

Imre F. Schene, Indi P. Joore, Rurika Oka, Michal Mokry, Anke H. M. Vugt, Ruben Boxtel, Hubert P. J. Doef, Luc J. W. Laan, Monique M. A. Verstegen, Peter M. Hasselt, Edward E. S. Nieuwenhuis and Sabine A. Fuchs ()
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Imre F. Schene: Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht
Indi P. Joore: Wilhelmina Children’s Hospital, University Medical Center Utrecht
Rurika Oka: Princess Maxima Center
Michal Mokry: Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht
Anke H. M. Vugt: Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht
Ruben Boxtel: Princess Maxima Center
Hubert P. J. Doef: University Medical Center Groningen
Luc J. W. Laan: Erasmus MC–University Medical Center Rotterdam
Monique M. A. Verstegen: Erasmus MC–University Medical Center Rotterdam
Peter M. Hasselt: Wilhelmina Children’s Hospital, University Medical Center Utrecht
Edward E. S. Nieuwenhuis: Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht
Sabine A. Fuchs: Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: Abstract Prime editing is a recent genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority of genetic defects. Here, we develop prime editing for primary adult stem cells grown in organoid culture models. First, we generate precise in-frame deletions in the gene encoding β‐catenin (CTNNB1) that result in proliferation independent of Wnt-stimuli, mimicking a mechanism of the development of liver cancer. Moreover, prime editing functionally recovers disease-causing mutations in intestinal organoids from patients with DGAT1-deficiency and liver organoids from a patient with Wilson disease (ATP7B). Prime editing is as efficient in 3D grown organoids as in 2D grown cell lines and offers greater precision than Cas9-mediated homology directed repair (HDR). Base editing remains more reliable than prime editing but is restricted to a subgroup of pathogenic mutations. Whole-genome sequencing of four prime-edited clonal organoid lines reveals absence of genome-wide off-target effects underscoring therapeutic potential of this versatile and precise gene editing strategy.

Date: 2020
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DOI: 10.1038/s41467-020-19136-7

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