Project Details

In Utero Gene Editing in the Murine Model of MPS-1 Using Lipid Nanoparticles

Cara Berkowitz, MD

Summary

BACKGROUND: Hurler disease (mucopolysaccharidosis-1, [MPS-1]) is a monogenic lysosomal storage disorder that manifests during childhood and leads to progressive, multisystem disease, including severe cardiovascular and pulmonary disease, coarse facial features, hepatosplenomegaly, cognitive impairment, corneal clouding, and musculoskeletal deformities. MPS-1 results from the inheritance of a single gene mutation with irreversible pathology that begins during fetal development and results in significant morbidity and early mortality GAP: In utero gene editing has the potential to provide a single, one-shot treatment to cure MPS-1 and various other monogenic diseases before manifestations of the disease are expressed. HYPOTHESIS: We hypothesize that in utero delivery of a CRISPR-mediated base editor via lipid nanoparticles can correct a common MPS-1 disease-causing mutation and mitigate the disease phenotype in the murine model of MPS-1. METHODS: We will develop our LNP vector in accordance with prior research protocols and published work from the lab and perform in utero intravascular administration of LNP complexes containing the ABE mRNA and MPS-1 targeting gRNA in fetal Idua-W392X mice. The experimental group will consist of Idua-W392X mice who receive in utero administration of LNP complexes containing the ABE mRNA and MPS-1 targeting gRNA and the control group will consist of uninjected Idua-W392X mice. RESULTS: Pending. IMPACT: This research is critical because it will demonstrate the safety and feasibility of therapeutic gene editing in a multisystem monogenic disease with implications for other genetic diseases with significant morbidity and mortality.