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

• Published in: Nature communications Vol. 12; no. 1; pp. 4291 - 16
• Main Authors: Bose, Sourav K, White, Brandon M, Kashyap, Meghana V, Dave, Apeksha, De Bie, Felix R, Li, Haiying, Singh, Kshitiz, Menon, Pallavi, Wang, Tiankun, Teerdhala, Shiva, Swaminathan, Vishal, Hartman, Heather A, Jayachandran, Sowmya, Chandrasekaran, Prashant, Musunuru, Kiran, Jain, Rajan, Frank, David B, Zoltick, Philip, Peranteau, William H
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.07.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adenine; Animals; Birth; Cardiomyocytes; Coronary artery disease; Disease; Disease Models, Animal; Editing; Heart diseases; Hepatocytes; Hepatocytes - metabolism; Humans; Lysosomal storage diseases; Lysosomal Storage Diseases - genetics; Lysosomal Storage Diseases - pathology; Morbidity; Mucopolysaccharidosis; Mutation; Mutation - genetics; Myocytes, Cardiac - metabolism; Organs; Pathology; Survival; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24443-8

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.