Author:
Su Jing,Jin Xiu,She Kaiqin,Liu Yi,Song Li,Zhao Qinyu,Xiao Jianlu,Li Ruiting,Deng Hongxin,Lu Fang,Yang Yang
Abstract
AbstractMucopolysaccharidosis type I (MPS I) is a severe disease caused by loss-of-function mutation 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 patients. Here, we used adenine base editing to directly convert A > G (TAG>TGG) in a newborn murine model harboring the 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 9 (AAV9) adenine base editor to circumvent the package size limit of AAV vectors. Intravenous injection of the AAV9-base editor system into MPS IH 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.
Funder
Joint Funds of the National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Molecular Medicine,Molecular Biology
Cited by
3 articles.
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