Poly(amine-co-ester)s for targeted delivery of gene editing agents to treat cystic fibrosis in animal models: SCGE Disease Models Studies Supplement

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Project title: Poly(amine-co-ester)s for targeted delivery of gene editing agents to treat cystic fibrosis in animal models: SCGE Disease Models Studies Supplement Participating SCGE award, investigators, and institutions: UG3/UH3 HL147352, Poly(amine-co-ester)s for targeted delivery in vivo of gene editing agents to bone marrow and lung, Yale University, MPI: WM Saltzman and PM Glazer. Co-I: ME Egan and R Fan Abstract: Over the past years, with support from the NIH Somatic Cell Gene Editing consortium, we have developed robust methods for synthesis of a family poly(amine-co-ester) (PACE) polymers that can be assembled into nanoparticles (NPs) that efficiently entrap nucleic acids. We have shown that these NPs are effective vectors for delivery of gene editing agents to the lung, and that the efficiency of editing—as well as the specific lung cell populations that are edited—can be optimized by the selection of optimal combinations of PACE variants, and by selection of the mode of administration, either intravenous (IV) or intratracheal (IN). Here we will test these optimized delivery systems for gene editing to treat cystic fibrosis (CF). For that purpose, we have in house two different, well-characterized animal models of CF: one contains the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation (F508del) classified as a Class II mutation and the other contains a common mutation that introduces a stop codon (W1282X) considered a Class I mutation. Gene editing in these animals will be detected by droplet digital PCR (ddPCR) and deep sequencing, as well as direct measurement of electrophysiology of the lung and the gut, using approaches we have developed.