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Development of Non-Viral, Trophoblast-Specific Gene Delivery for Placental Therapy.

Abd Ellah N, Taylor L, Troja W, Owens K, Ayres N, Pauletti G, Jones H - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Offspring birthweights at delivery were the same in Sham-operated, Internal control and UABL + PLAC1-HuIGF-1 nanoparticle treated group, however the Uterine Artery Branch Ligation, and Cyp19a-HuIGF-1 nanoparticle treated groups had significantly lower birthweights.N>6 dams per group, ANOVA<0.001, post-hoc Tukeys *<0.05, **<0.01.
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pone.0140879.g004: Offspring birthweights at delivery were the same in Sham-operated, Internal control and UABL + PLAC1-HuIGF-1 nanoparticle treated group, however the Uterine Artery Branch Ligation, and Cyp19a-HuIGF-1 nanoparticle treated groups had significantly lower birthweights.N>6 dams per group, ANOVA<0.001, post-hoc Tukeys *<0.05, **<0.01.

Mentions: Offspring from all treatments were delivered and viable at day 20 of gestation by caesarian section. Numbers of pups per litter at delivery were not altered by UABL or nanoparticle treatment compared to litter size recorded at time of surgery. Offspring weights of those whose placentas had received the PLAC1-IGF-1(1.04±0.05) nanoparticle showed significantly (p<0.05, ANOVA, n> 6 per group) higher birth weights than those in the UABL group (0.82±0.04) or those who underwent treatment with the CyP19a-923-IGF-1 (0.85±0.65) nanoparticle (Fig 4A). PLAC1-IGF-1 nanoparticle-treated pups weighed the same as the sham-operated and internal controls (1.13±0.04, and 1.11±0.05, Fig 4).


Development of Non-Viral, Trophoblast-Specific Gene Delivery for Placental Therapy.

Abd Ellah N, Taylor L, Troja W, Owens K, Ayres N, Pauletti G, Jones H - PLoS ONE (2015)

Offspring birthweights at delivery were the same in Sham-operated, Internal control and UABL + PLAC1-HuIGF-1 nanoparticle treated group, however the Uterine Artery Branch Ligation, and Cyp19a-HuIGF-1 nanoparticle treated groups had significantly lower birthweights.N>6 dams per group, ANOVA<0.001, post-hoc Tukeys *<0.05, **<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608830&req=5

pone.0140879.g004: Offspring birthweights at delivery were the same in Sham-operated, Internal control and UABL + PLAC1-HuIGF-1 nanoparticle treated group, however the Uterine Artery Branch Ligation, and Cyp19a-HuIGF-1 nanoparticle treated groups had significantly lower birthweights.N>6 dams per group, ANOVA<0.001, post-hoc Tukeys *<0.05, **<0.01.
Mentions: Offspring from all treatments were delivered and viable at day 20 of gestation by caesarian section. Numbers of pups per litter at delivery were not altered by UABL or nanoparticle treatment compared to litter size recorded at time of surgery. Offspring weights of those whose placentas had received the PLAC1-IGF-1(1.04±0.05) nanoparticle showed significantly (p<0.05, ANOVA, n> 6 per group) higher birth weights than those in the UABL group (0.82±0.04) or those who underwent treatment with the CyP19a-923-IGF-1 (0.85±0.65) nanoparticle (Fig 4A). PLAC1-IGF-1 nanoparticle-treated pups weighed the same as the sham-operated and internal controls (1.13±0.04, and 1.11±0.05, Fig 4).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus