title: Development of Non-Viral, Trophoblast-Specific Gene Delivery for Placental Therapy.
abstract: Low birth weight is associated with both short term problems and the fetal programming of adult onset diseases, including an increased risk of obesity, diabetes and cardiovascular disease. Placental insufficiency leading to intrauterine growth restriction (IUGR) contributes to the prevalence of diseases with developmental origins. Currently there are no therapies for IUGR or placental insufficiency. To address this and move towards development of an in utero therapy, we employ a nanostructure delivery system complexed with the IGF-1 gene to treat the placenta. IGF-1 is a growth factor critical to achieving appropriate placental and fetal growth. Delivery of genes to a model of human trophoblast and mouse placenta was achieved using a diblock copolymer (pHPMA-b-pDMAEMA) complexed to hIGF-1 plasmid DNA under the control of trophoblast-specific promoters (Cyp19a or PLAC1). Transfection efficiency of pEGFP-C1-containing nanocarriers in BeWo cells and non-trophoblast cells was visually assessed via fluorescence microscopy. In vivo transfection and functionality was assessed by direct placental-injection into a mouse model of IUGR. Complexes formed using pHPMA-b-pDMAEMA and CYP19a-923 or PLAC1-modified plasmids induce trophoblast-selective transgene expression in vitro, and placental injection of PLAC1-hIGF-1 produces measurable RNA expression and alleviates IUGR in our mouse model, consequently representing innovative building blocks towards human placental gene therapies.
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, United States of America; Faculty of Pharmacy, Assiut University, 71515, Assiut, Arab Republic of Egypt.
authors.forename: Noura
authors.initials: N
authors.lastname: Abd Ellah
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH, 45221, United States of America.
authors.forename: Leeanne
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Divisions of General and Thoracic Surgery and Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
authors.forename: Weston
authors.initials: W
authors.lastname: Troja
authors.affiliation: Divisions of General and Thoracic Surgery and Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Owens
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH, 45221, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Ayres
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, United States of America.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pauletti
authors.affiliation: Divisions of General and Thoracic Surgery and Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Jones
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D010927:Placental Insufficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology
chemical_list: C583557:IGF1 protein, human; C415583:PLAC1 protein, human; D011257:Pregnancy Proteins; D007334:Insulin-Like Growth Factor I; D001141:Aromatase; C561410:CYP19A1 protein, human