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. 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


Treatment of a Metabolic Liver Disease by in Vivo Genome Base Editing in Adult Mice

Lukas Villiger et al. Nat Med. .


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.

Comment in

  • Towards therapeutic base editing.
    Seo H, Kim JS. Seo H, et al. Nat Med. 2018 Oct;24(10):1493-1495. doi: 10.1038/s41591-018-0215-3. Nat Med. 2018. PMID: 30297902 No abstract available.
  • Lab Anim (NY). 2019 Jan;48(1):27
  • Therapeutic gene editing, making a point.
    Smits AM. Smits AM. Cardiovasc Res. 2019 Mar 15;115(4):e39-e40. doi: 10.1093/cvr/cvz038. Cardiovasc Res. 2019. PMID: 30824914 Free PMC article. No abstract available.

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