Fetal Base Editing Ameliorates Cardiac Pathology in a Mouse Model of Mucopolysaccharidosis Type I
Sourav K. Bose1,2, Brandon White2, Meaghan Kashyap2, Haiying Li2, Philip W. Zoltick2, William H Peranteau2
1Brigham and Women's Hospital, Boston, MA, 2Children's Hospital of Philadelphia, Philadelphia, PA
Background: MPS-IH is caused by a G-to-A mutation in the IDUA gene which results in undetectable IDUA enzyme, the buildup of glycosaminoglycans (GAG), and death by age 10. GAG deposition in cardiac muscle, mitral/aortic valves, and the aortic wall leads to cardiomyopathy, root dilation, and valvular insufficiency. Fetal gene editing offers the potential to correct the mutation before the onset of irreversible pathology.
Methods: We delivered an adenine base editor and guide RNA targeting the murine MPS-IH mutation in embryonic day 15.5 fetuses via the vitelline vein, a hepatic tributary. Echocardiography (TTE) was assessed at 4 and 6 months. At 6 months, cardiac enzyme and GAG levels were measured. Cardiac cell populations were isolated using flow cytometry to evaluate gene editing. Tissue structural morphology was assessed with Alcian blue and Massonís trichrome stains.
Results: Next generation sequencing demonstrated efficient gene editing in cardiac myocytes(~12.6%), endothelial cells(~3.0%), and fibroblasts(~2.3%). TTE demonstrated normalized function: reduced LV systolic/diastolic diameters and increased ejection fraction and fractional shortening. Control mice with aortic diameters>3.5cm had 100% mortality. In contrast no treated mice developed aortic dilation, and mortality was 0%. At 6 months, treated mice had robust cardiac enzyme activity, reduced GAGS, reduced valvular thickening, and improved aortic architecture.
Conclusion: Fetal gene editing in the MPS-IH mouse normalizes cardiac function and confers survival. Due to early onset of cardiac pathology associated with significant mortality, in utero treatment of MPS-IH has relevance for clinical translation. Although this proof-of-concept is promising, further work to characterize the safety of fetal gene editing is essential.
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