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Nat Med. 2018 Oct;24(10):1519-1525. doi: 10.1038/s41591-018-0209-1. Epub 2018 Oct 8.

Treatment of a metabolic liver disease by in vivo genome base editing in adult mice.

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Department Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Division of Metabolism, University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland.
SIB Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland.
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
Swiss Newborn Screening Laboratory, University Children's Hospital, Zurich, Switzerland.
Zurich Center for Integrative Human Physiology, Zurich, Switzerland.
Neuroscience Center Zurich, Zurich, Switzerland.
Department Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.


CRISPR-Cas-based genome editing holds great promise for targeting genetic disorders, including inborn errors of hepatocyte metabolism. Precise correction of disease-causing mutations in adult tissues in vivo, however, is challenging. It requires repair of Cas9-induced double-stranded DNA (dsDNA) breaks by homology-directed mechanisms, which are highly inefficient in nondividing cells. Here we corrected the disease phenotype of adult phenylalanine hydroxylase (Pah)enu2 mice, a model for the human autosomal recessive liver disease phenylketonuria (PKU)1, using recently developed CRISPR-Cas-associated base editors2-4. These systems enable conversion of C∙G to T∙A base pairs and vice versa, independent of dsDNA break formation and homology-directed repair (HDR). We engineered and validated an intein-split base editor, which allows splitting of the fusion protein into two parts, thereby circumventing the limited cargo capacity of adeno-associated virus (AAV) vectors. Intravenous injection of AAV-base editor systems resulted in Pahenu2 gene correction rates that restored physiological blood phenylalanine (L-Phe) levels below 120 µmol/l [5]. We observed mRNA correction rates up to 63%, restoration of phenylalanine hydroxylase (PAH) enzyme activity, and reversion of the light fur phenotype in Pahenu2 mice. Our findings suggest that targeting genetic diseases in vivo using AAV-mediated delivery of base-editing agents is feasible, demonstrating potential for therapeutic application.

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