Project Details

In-Utero Gene Editing for Duchenne Muscular Dystrophy with Systemically Delivered Lipid Nanoparticles

Natalie Berger, MD

Summary

BACKGROUND: Duchenne muscular dystrophy (DMD), a recessive X-linked neuromuscular disorder, is the most common muscular dystrophy in children affecting 1 in 5000 boys and ~20,000 babies worldwide. Patients with DMD are usually wheelchair bound by teenage years and die by their 30s. CRISPR-Cas9 mediated exon skipping of dystrophin gene exons harboring mutations represents a one-and-done therapy for patients with DMD. GAP: Our proposal seeks to address the current inability in the field to efficiently deliver CRISPR gene editing technology for therapeutic editing to muscle cells in vivo via nonviral (LNP) delivery approaches. HYPOTHESIS: We hypothesize that specific timing of LNP administration and LNP composition will enhance myocyte targeting. We hypothesize that this approach can be used to develop an in vivo gene editing therapy for DMD that will also serve as a platform on which to develop gene editing therapies for other monogenic muscle diseases. METHODS: We will develop and optimize LNP mediated mRNA delivery to myocytes and muscle stem cells in fluorescent reporter mice and assess in vivo CRISPR editing for exon skipping in the dystrophin gene following LNP administration in mouse models at different developmental time points. Multiple organs, including the heart and skeletal muscle, will be assessed for MRNA delivery and editing at short and long-term time points following injection. RESULTS: Pending. IMPACT: Success in completing this translational project will provide critical information on the feasibility of an in vivo approach to successfully and safely deliver gene editing technology to myocytes via LNPs. Furthermore, these studies will provide the foundation to develop a one-shot, long-term therapy that mitigates lethal monogenic muscle diseases including DMD. Website Link: https://www.research.chop.edu/peranteau-laboratory