PT  - JOURNAL ARTICLE
AU  - Jing Su
AU  - Xiu Jin
AU  - Kaiqin She
AU  - Yi Liu
AU  - Xiaomei Zhong
AU  - Qinyu Zhao
AU  - Jianlu Xiao
AU  - Ruiting Li
AU  - Hongxin Deng
AU  - Yang Yang
TI  - <em>In vivo</em> adenine base editing corrects newborn murine model of Hurler syndrome
AID  - 10.1101/2021.10.16.464213
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.16.464213
4099  - http://biorxiv.org/content/early/2021/10/16/2021.10.16.464213.short
4100  - http://biorxiv.org/content/early/2021/10/16/2021.10.16.464213.full
AB  - Mucopolysaccharidosis type I (MPS I) is a severe disease caused by loss-of-function mutations variants in the α-L-iduronidase (IDUA) gene. In vivo genome editing represents a promising strategy to correct IDUA mutations, and has the potential to permanently restore IDUA function over the lifespan of the patients. Here, we used adenine base editing to directly convert A>G (TAG>TGG) in newborn murine model harboring Idua-W392X mutation, which recapitulates the human condition and is analogous to the highly prevalent human W402X mutation. We engineered a split-intein dual-adeno-associated virus (AAV) 9 in vivo adenine base editor to circumvent the package size limit of AAV vectors. Intravenous injection of AAV9-base editor system into MPS I newborn mice led to sustained enzyme expression sufficient for correction of metabolic disease (GAGs substrate accumulation) and prevention of neurobehavioral deficits. We observed a reversion of the W392X mutation in 22.46±6.74% of hepatocytes, 11.18±5.25% of heart and 0.34±0.12% of brain, along with decreased GAGs storage in peripheral organs (liver, spleen, lung and kidney). Collectively, these data showed the promise of a base editing approach to precisely correct a common genetic cause of MPS I in vivo and could be broadly applicable to the treatment of a wide array of monogenic diseases.Competing Interest StatementThe authors have declared no competing interest.