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Development of Non-Viral, Trophoblast-Specific Gene Delivery for Placental Therapy
Noura Abd Ellah1, Leeanne Taylor2, Weston Troja3
1James 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.
Insights
This study introduces a novel nanostructure gene delivery system using IGF-1 to treat placental insufficiency and intrauterine growth restriction (IUGR). The therapy successfully alleviated IUGR in a mouse model, offering hope for future in utero treatments.
Area of Science:
- Biomedical Engineering
- Reproductive Biology
- Gene Therapy
Background:
- Low birth weight and placental insufficiency contribute to developmental origins of adult diseases.
- Intrauterine growth restriction (IUGR) is a significant concern with no current therapies.
- Fetal programming links early development to long-term health risks like obesity and diabetes.
Purpose of the Study:
- To develop an in utero gene therapy for placental insufficiency and IUGR.
- To utilize a nanostructure delivery system for targeted gene delivery to the placenta.
- To investigate the therapeutic potential of Insulin-like Growth Factor 1 (IGF-1) gene therapy.
Main Methods:
- A diblock copolymer (pHPMA-b-pDMAEMA) nanostructure was complexed with the hIGF-1 gene.
- Trophoblast-specific promoters (Cyp19a or PLAC1) were used for gene expression control.
- In vitro transfection efficiency was assessed in BeWo cells; in vivo functionality was tested via placental injection in a mouse model of IUGR.
Main Results:
- Nanocarriers demonstrated trophoblast-selective transgene expression in vitro.
- Placental injection of PLAC1-hIGF-1 resulted in measurable RNA expression in vivo.
- The IGF-1 gene therapy successfully alleviated IUGR in the mouse model.
Conclusions:
- The developed nanostructure delivery system shows promise for placental gene therapy.
- Targeted IGF-1 gene delivery can effectively treat placental insufficiency and IUGR.
- This approach represents a significant step towards innovative in utero therapeutic strategies.
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.
