| Literature DB >> 34257302 |
Sourav K Bose1,2, Brandon M White1,2, Meghana V Kashyap1, Apeksha Dave1,2, Felix R De Bie1,2, Haiying Li1,2, Kshitiz Singh1,2, Pallavi Menon1,2, Tiankun Wang1,2, Shiva Teerdhala1,2, Vishal Swaminathan1,2, Heather A Hartman1,2, Sowmya Jayachandran3,4, Prashant Chandrasekaran3,4, Kiran Musunuru5,6,7, Rajan Jain6,8, David B Frank3,4,5, Philip Zoltick1,2, William H Peranteau9,10.
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.Entities:
Year: 2021 PMID： 34257302 DOI： 10.1038/s41467-021-24443-8
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919