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, William H Peranteau

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number4291
Number of pages16
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 13 Jul 2021

Bibliographical note

© 2021. The Author(s).

Keywords

  • Animals
  • Disease Models, Animal
  • Hepatocytes/metabolism
  • Humans
  • Lysosomal Storage Diseases/genetics
  • Mutation/genetics
  • Myocytes, Cardiac/metabolism

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