Nanoparticle‐mediated transgene expression of insulin‐like growth factor 1 in the growth restricted guinea pig placenta increases placenta nutrient transporter expression and fetal glucose concentrations

Abstract

Fetal growth restriction (FGR) significantly contributes to neonatal and perinatal morbidity and mortality. Currently, there are no effective treatment options for FGR during pregnancy. We have developed a nanoparticle gene therapy targeting the placenta to increase expression of human insulin-like growth factor 1 (hIGF-1) to correct fetal growth trajectories. Using the maternal nutrient restriction (MNR) guinea pig model of FGR, an ultrasound-guided, intra-placental injection of non-viral, polymer-based nanoparticle gene therapy containing plasmid with the hIGF-1 gene and placenta-specific Cyp19a1 promotor was administered at mid-pregnancy. Sustained hIGF-1 expression was confirmed in the placenta five days after treatment. Whilst gene therapy treatment did not change fetal weight, circulating fetal glucose concentration were 33-67% higher. This was associated with increased expression of glucose and amino acid transporters in the placenta. Additionally, nanoparticle gene therapy treatment increased the fetal capillary volume density in the placenta, and reduced interhaemal distance between maternal and fetal circulation.Overall, our findings, that gene therapy treatment results in changes to glucose transporter expression and increases fetal glucose concentrations within a short time period, highlights the translational potential this treatment could have in correcting impaired placental nutrient transport in human pregnancies complicated by FGR.

Placental nanoparticle gene therapy normalizes gene expression changes in the fetal liver associated with fetal growth restriction in a fetal sex-specific manner

“…The molecular and physiological mechanisms behind the normalization of Hif1α and Tnfα are yet to be determined, however suggest the ability for the hIGF-1 nanoparticle treatment of the placenta to result in reduced hypoxia in fetal livers. Our analysis of placental morphology with hIGF-1 nanoparticle treatment indicates reduced interhaemal distance between maternal and fetal circulation likely resulting in increased oxygen diffusion 20 , and a possible mechanism by which expression of Hif1α and Tnfα reduced.…”

“…We have previously shown in the guinea pig MNR model of FGR, efficient uptake of our hIGF-1 nanoparticle gene therapy into the guinea pig placenta, and no transfer of nanoparticle or hIGF-1 plasmid into fetal circulation 20 . In the present study, we aimed to characterize the effects of FGR on hepatic gluconeogenesis gene expression at the initial stages of FGR establishment in the fetal guinea pig, and determine whether treatment of the placenta with our hIGF-1 nanoparticle gene therapy could resolve differences in hepatic gluconeogenesis gene expression in the FGR fetus.…”

“…Detailed methods on the synthesis of the (PHPMA115-b-PDMAEMA115) copolymer, and nanoparticle formation can be found in Wilson et al, 2022 20 . Briefly, plasmids containing the human IGF-1 gene under control of the trophoblast-specific CYP19A1 promotor were mixed with the non-viral PHPMA115-b-PDMAEMA115 co-polymer for 1 h at room temperature to form the hIGF-1 nanoparticle.…”

“…We have developed the use of a polymer-based nanoparticle that facilitates nonviral, transient (does not integrate into the genome), gene delivery specifically to the placenta 16,17 . Using a biosynthetic HPMA-DMEAMA (N-(2-hydroxypropyl) methacrylamide-2-(dimethylamino)ethyl methacrylate) co-polymer, complexed with a plasmid containing the human insulin-like 1 growth factor (hIGF-1) gene under the control of trophoblast specific promotors (PLAC1, CYP19A1), we have successful shown efficient nanoparticle uptake into human syncytiotrophoblast ex vivo 17 as well as in vivo using animal models 16,[18][19][20] . Short-term effects of hIGF-1 gene therapy results in increased placental expression of glucose and amino acid transporters, maintenance of normal fetal growth under FGR conditions, and increased fetal glucose concentrations 16,[18][19][20] .…”

Placental treatment with insulin-like growth factor 1 via nanoparticle differentially impacts vascular remodeling factors in guinea pig sub-placenta/decidua

“…Fetal growth positively correlates with maternal IGF-1 concentrations (Chellakooty, Vangsgaard et al 2004), and both maternal serum levels of IGF-1 and placenta expression of IGF-1R are decreased in FGR (Holmes, Montemagno et al 1997, Laviola, Perrini et al 2005). Additionally, we have previously shown that treatment of the placenta with a non-viral, polymer based, nanoparticle gene therapy that specifically increases human IGF-1 ( hIGF-1 ) in trophoblast, maintains fetal growth in a surgically-ligated FGR mouse model, and increases nutrient transporter expression (Abd Ellah, Taylor et al 2015, Wilson, Owens et al 2020, Wilson, Lampe et al 2021). Placenta treatment with the hIGF-1 nanoparticle does not adversely impact maternal or fetal outcomes, and cannot cross the placenta into fetal circulation (Wilson, Lampe et al 2021, Wilson, Stephens et al 2021).…”