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

Sourav K Bose,Rajan Jain,Brandon M White,Apeksha Dave,Meghana V Kashyap,William H Peranteau,Pallavi Menon,Heather A Hartman,Sowmya Jayachandran,Haiying Li,Kiran Musunuru,Felix R De Bie,Philip Zoltick,Prashant Chandrasekaran,Kshitiz Singh,David B Frank,Vishal Swaminathan,Tiankun Wang,Shiva Teerdhala

doi:10.1038/s41467-021-24443-8

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.

Highlights

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology
We evaluate associated virus serotype 9 (AAV9)-mediated in utero intravascular delivery of an adenine base editor (ABE) to correct the G→A mutation and rescue the disease phenotype in the Idua-W392X MPS-IH mouse model which recapitulates W402X MPS-IH disease in humans[38]
This approach has previously demonstrated the ability to produce a functioning adenine base editor in vivo[39]. To initially evaluate this approach in utero, standard gene editing was performed in the tractable R26mTmG/+ mouse model wherein deletion of a loxP-flanked membrane tomato cassette and subsequent nonhomologous endjoining (NHEJ) switches native red fluorescence to green

Summary

Introduction

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. 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. Lysosomal storage disorders affect multiple organs, have limited treatments, and have pathology that begins before birth[1]. Prenatal cardiac dysfunction has led to myocardial hypertrophy and early postnatal death in MPS-IH9

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Conclusion