In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease

Sourav K. Bose, Brandon M. White, Meghana V. Kashyap, Apeksha Dave, Felix R. De Bie, Haiying Li, Kshitiz Singh, Pallavi Menon, Tiankun Wang, Shiva Teerdhala, Vishal Swaminathan, Heather A. Hartman, Sowmya Jayachandran, Prashant Chandrasekaran, Kiran Musunuru, Rajan Jain, David B. Frank, Philip Zoltick and William H. Peranteau ()
Additional contact information
Sourav K. Bose: Children’s Hospital of Philadelphia
Brandon M. White: Children’s Hospital of Philadelphia
Meghana V. Kashyap: Children’s Hospital of Philadelphia
Apeksha Dave: Children’s Hospital of Philadelphia
Felix R. De Bie: Children’s Hospital of Philadelphia
Haiying Li: Children’s Hospital of Philadelphia
Kshitiz Singh: Children’s Hospital of Philadelphia
Pallavi Menon: Children’s Hospital of Philadelphia
Tiankun Wang: Children’s Hospital of Philadelphia
Shiva Teerdhala: Children’s Hospital of Philadelphia
Vishal Swaminathan: Children’s Hospital of Philadelphia
Heather A. Hartman: Children’s Hospital of Philadelphia
Sowmya Jayachandran: Perelman School of Medicine at the University of Pennsylvania
Prashant Chandrasekaran: Perelman School of Medicine at the University of Pennsylvania
Kiran Musunuru: Perelman School of Medicine at the University of Pennsylvania
Rajan Jain: Perelman School of Medicine at the University of Pennsylvania
David B. Frank: Perelman School of Medicine at the University of Pennsylvania
Philip Zoltick: Children’s Hospital of Philadelphia
William H. Peranteau: Children’s Hospital of Philadelphia

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases.

Date: 2021
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DOI: 10.1038/s41467-021-24443-8

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