Nanoparticles for Site-Specific Genome Editing in Utero

Yale University, New Haven CT

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Abstract

PROJECT SUMMARY, RICCIARDI BACKGROUND AND CENTRAL HYPOTHESIS: An estimated 8 million children around the world are born annually with severe genetic disorders or birth defects. Many diseases that cause considerable perinatal and pediatric morbidity are monogenic and can be diagnosed early in pregnancy. Despite early diagnosis, genetic disease continues to contribute significantly to childhood morbidity and mortality as most currently available treatments and therapies focus on enzyme replacement or the management of symptoms and do not provide correction of the underlying genetic mutation. Early intervention through intrauterine gene therapy, however, could correct the genetic defect during early stages of pathogenesis, potentially allowing for normal organ development, functional disease improvement, or cure. It has been shown that site-specific genome modification to correct disease-causing mutations can be coordinated efficiently and safely in postnatal animals via the in vivo delivery polymeric, biodegradable nanoparticles loaded with triplex-forming peptide nucleic acids (PNAs) and short DNA fragments. We hypothesize that we can use this synthetic nanoparticle (NP) system in a novel and potentially transformative approach ? to safely produce site-specific correction of genetic mutations in the chromosomes of fetal cells, in utero. SPECIFIC AIMS: First, we will study the biodistribution and delivery kinetics of fluorescent nanoparticles at multiple gestational ages after two methods of in utero NP administration. Next, we will use a transgenic reporter model to determine the feasibility of sustained gene editing after in utero delivery of NPs loaded with PNAs and donor DNA. Finally, we will determine if in utero delivery of nanoparticles loaded with PNAs and donor DNAs targeting the ?-globin locus can result in site-specific gene correction and disease improvement in a mouse model of ?-thalassemia. PUBLIC HEALTH REVELANCE: This project will demonstrate the feasibility of treating genetic blood diseases by site-specific, fetal gene editing in utero and will help establish the framework for an innovative, clinically translatable system for targeted gene therapy in human fetuses.