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

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.

Recent Advances in CRISPR/Cas9-Based Genome Editing Tools for Cardiac Diseases

“…Considering the natural characteristics of the developing fetus, as well as the timing of the onset of some diseases, prenatal base editing might become an attractive therapeutic approach, and this study confirms the potential of this system. Additionally, the authors assessed the post-natal effect of the ABE treatment, confirming the attenuation of the disease progression in the treated mice at 10 weeks of age [47].…”

“…Moreover, an SpCas9 immune response was observed after postnatal, but not in utero, adenoviral delivery of an SpCas9-based CBE [69]. Accordingly, the presence of anti-SpCas9 antibodies was demonstrated in the serum of adult but not fetal ABE recipients [47].…”

“…An outstanding study recently demonstrated the potential of base editing for the correction of disease-causing mutations in utero, thus preventing the onset of certain pathologies [47]. The AAV9-mediated in utero intravascular delivery of an ABE successfully corrected a nonsense Idua gene mutation in a mouse model of mucopolysaccharidosis type I (MPS-IH), a lysosomal storage disease affecting multiple organs, including the heart.…”

DNA base editing in nuclear and organellar genomes

“…Recently, this BEbased treatment has received clearance for clinical trial application and plans to initiate a Phase 1 clinical trial in patients in mid-2022 have been announced (https://ir.vervetx.com/newsreleases/news-release-details/verve-therapeutics-announces-clearance-first-verve-101-clinical). Additional hereditary diseases that have been treated by BEs in proof-of-concept studies include Duchenne muscular dystrophy [123], albinism [123,124], Hutchinson-Gilford progeria syndrome [125], and several other metabolic diseases [36,126]. These examples show the great potential of BEs for the future cure of genetic disorders.…”

Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

“…After intranasal administration, the enzymatic activity in the olfactory bulb recovered to 100-fold compared to the control, maintaining the same levels in the rest of the brain [ 98 ]. Recent studies reported the efficacy of the in utero administration of viral vectors in the mouse, demonstrating promising outcomes [ 99 , 100 ].…”