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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

Placental morphology in the Labyrinthine (L) zone in (A) Sham, (B) UABL,(C) NP-PLAC1-hIGF-1treated groups is similar whereas differences in morphology can be seen in the NP-Cyp19a-hIGF-1 (D) treated group. (Magnification 40X). (E) The ratio of placental Junctional zone (Jz) area to Labyrinthine zone (Lz) area demonstrates significant expansion of the junctional zone in placentas treated with NP-Cyp19a-hIGF-1.
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pone.0140879.g005: Placental morphology in the Labyrinthine (L) zone in (A) Sham, (B) UABL,(C) NP-PLAC1-hIGF-1treated groups is similar whereas differences in morphology can be seen in the NP-Cyp19a-hIGF-1 (D) treated group. (Magnification 40X). (E) The ratio of placental Junctional zone (Jz) area to Labyrinthine zone (Lz) area demonstrates significant expansion of the junctional zone in placentas treated with NP-Cyp19a-hIGF-1.

Mentions: There were no differences in placental weights between sham and UABL groups as previously reported by our group [24] or between sham and any of the nanoparticle-treated groups (0.09g ± 0.01 vs. 0.08g ± 0.02 vs. 0.10g ± 0.03, n>5 per group). Labyrinth depth was significantly reduced in the UABL group as previously reported, however in the NP-PLAC1-IGF-1 (1.15mm ± 0.85) treated placentas it was the same as the sham group (1.07mm ± 0.09) and significantly increased compared to the UABL group (0.68mm ± 0.65) (p<0.05, n = 5 per group). There was no evidence of inflammation or immune cell infiltration seen in the sham (Fig 5A), UABL (Fig 5B) or NP-PLAC1-IGF-1 (Fig 5C) injected placentas following H&E staining. However, NP-CyP19a-hIGF-1 placentas showed evidence of morphological disturbance with disorganization in the labyrinth zone (Fig 5D) and expansion of the junctional zone as demonstrated by the altered ratio of labyrinth to junctional zone (Fig 5E), as shown previously in some transgenic strains [25].


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)

Placental morphology in the Labyrinthine (L) zone in (A) Sham, (B) UABL,(C) NP-PLAC1-hIGF-1treated groups is similar whereas differences in morphology can be seen in the NP-Cyp19a-hIGF-1 (D) treated group. (Magnification 40X). (E) The ratio of placental Junctional zone (Jz) area to Labyrinthine zone (Lz) area demonstrates significant expansion of the junctional zone in placentas treated with NP-Cyp19a-hIGF-1.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140879.g005: Placental morphology in the Labyrinthine (L) zone in (A) Sham, (B) UABL,(C) NP-PLAC1-hIGF-1treated groups is similar whereas differences in morphology can be seen in the NP-Cyp19a-hIGF-1 (D) treated group. (Magnification 40X). (E) The ratio of placental Junctional zone (Jz) area to Labyrinthine zone (Lz) area demonstrates significant expansion of the junctional zone in placentas treated with NP-Cyp19a-hIGF-1.
Mentions: There were no differences in placental weights between sham and UABL groups as previously reported by our group [24] or between sham and any of the nanoparticle-treated groups (0.09g ± 0.01 vs. 0.08g ± 0.02 vs. 0.10g ± 0.03, n>5 per group). Labyrinth depth was significantly reduced in the UABL group as previously reported, however in the NP-PLAC1-IGF-1 (1.15mm ± 0.85) treated placentas it was the same as the sham group (1.07mm ± 0.09) and significantly increased compared to the UABL group (0.68mm ± 0.65) (p<0.05, n = 5 per group). There was no evidence of inflammation or immune cell infiltration seen in the sham (Fig 5A), UABL (Fig 5B) or NP-PLAC1-IGF-1 (Fig 5C) injected placentas following H&E staining. However, NP-CyP19a-hIGF-1 placentas showed evidence of morphological disturbance with disorganization in the labyrinth zone (Fig 5D) and expansion of the junctional zone as demonstrated by the altered ratio of labyrinth to junctional zone (Fig 5E), as shown previously in some transgenic strains [25].

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