Sourav K. Bose (1,2), Brandon M. White (1,2), Meghana V. Kashyap (1), Apeksha Dave (1,2), Felix R. De Bie (1,2), Haiying Li (1,2), Kshitiz Singh (1,2) , Pallavi Menon (1,2), Tiankun Wang (1,2), Shiva Teerdhala (1,2), Vishal Swaminathan (1,2), Heather A. Hartman (1,2), Sowmya Jayachandran (3,4), Prashant Chandrasekaran (3,4), Kiran Musunuru (5,6,7), Rajan Jain (6,8), David B. Frank (3,4,5), Philip Zoltick (1,2), William H. Peranteau (1,2)
Nature Communications, 12, Issue 4291, July 2021. DOI: 10.1038/s41467-021-24443-8

Keywords

Cardiology; CRISPR-Cas9 genome editing; Molecular medicine

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.

How Our Software Was Used

Dragonfly was used to analyse DICOM images.

Author Affiliation

(1) Center for Fetal Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
(2) Division of General, Thoracic and Fetal Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
(3) Division of Pediatric Cardiology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
(4) Center for Pulmonary Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
(5) Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
(6) Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
(7) Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
(8)Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.