A pioneering therapy aimed at reversing a leading cause of stillbirth and premature birth has shown promising results in animal studies, led by decades of research on the placenta
Study:Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model. Image Credit: r.classen / Shutterstock.com
A recent Gene Therapy study investigates the effectiveness of placental nano-based insulin-like 1 growth factor (IGF1) gene therapy to correct fetal growth restriction (FGR).
FGR: Prevalence and causes
Approximately 10% of human newborns are born premature or too small, which accounts for over 2.5 million stillbirths and 15 million preterm deliveries. Surviving FGR neonates are at a greater risk of complications and comorbidities linked to developmental origins of health and disease (DOHaD). These complications can lead to cognitive deficits, cardiovascular disease, and obesity in children or adults.
Currently, there are no treatments for FGR or conditions like placental insufficiency, during which the placenta fails to transfer sufficient nutrients and oxygen to the fetus for its proper growth. Although significant progress has been made in neonatal care, scientists have primarily focused on achieving normal gestational length for optimal growth.
Intrinsic idiopathic causes of FGR include placental malformation or fetal genetic abnormalities. Extrinsic causes may include maternal stress or maternal comorbidities such as malnutrition, diabetes, or drug/alcohol use.
The placenta is the key communication link between the fetus and mother; therefore, this organ could be an effective therapeutic target for treating FGR. Correcting FGR factors could reduce the number of premature neonates, stillbirths, and adult comorbidities.
Human FGR cases have been associated with downregulation of IGF1. Previous studies have shown that the IGF signaling axis is a prime regulator of placental development and a crucial hormone for the entire gestation period.
About the study
The current study investigates the ability of a biodegradable nano-based system to deliver a plasmid containing the IGF1 gene in the placental trophoblast to correct FGR and placental insufficiency. The nanobased system was developed by complexing a non-viral co-polymer with plasmids containing the IGF1 gene under the control of CYP19A1, a trophoblast-specific promoter.
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A guinea pig model of FGR was used to assess the effectiveness of nanoparticle-mediated IGF1 gene therapy in improving fetal growth. Herein, the effectiveness of repeated nanoparticle-mediated IGF1 treatments in restoring aberrant placental physiology and function was determined, which could enable placental correction of FGR.
Guinea pigs were divided into different treatment groups, including control, maternal nutrient restriction (MNR) diet, and MNR + IGF1 groups. After a two-week acclimation period and proper diet program, female guinea pigs were anesthetized, during which either the nanoparticle or sham treatment was delivered to the placenta through ultrasound-guided intra-placental injection. This treatment was repeated every eight days starting from gestation day (GD) 36.
Females and other male littermates were also indirectly exposed to circulating nanoparticles. Dams were sacrificed at GD 6,0 and the placenta, subplacenta, and decidua were obtained for further analysis.
Study findings
Repeated nanoparticle-mediated IGF1 treatments from mid-pregnancy to near-term exhibited no adverse health complications, placental hemorrhage, or fetal loss. No difference in average litter size was observed between control and MNR diets. Most dams became pregnant during the first mating attempts, whereas the remaining became pregnant on the second mating.
Repeated nanoparticle treatments with the human IGF1 gene induced human IGF1 (hIGF1) messenger ribonucleic acid (mRNA) expression in the directly injected or indirectly exposed placentas. This expression was absent in the control group receiving sham treatment. Quantitative polymerase chain reaction (qPCR) assay revealed that indirectly exposed placentas had less hIGF1 expression than directly injected placenta.
As compared to controls, MNR placentas in males exhibited reduced endogenous levels of guinea pig Igf1 (gpIgf1). However, no significant difference in endogenous gpIgf1 was observed in MNR + IGF1 placentas and controls.
Sexually dimorphic changes were found in Igf2, Igf1 receptor (Igf1R), and Igf binding protein 3 (IgfBP3). Although indirect nanoparticle-mediated IGF1 exposure did not indicate an impact on Igf2 expression, direct IGF1 treatment in the male placenta led to a significant increase in Igf2 expression.
Fetuses whose placenta received repeated nanoparticle-mediated IGF1 injection were at a greater weight than MNR and control males. A significant association between hIGF1 levels in the placenta and male fetal weight was observed.
Blood analysis revealed reduced male fetal blood glucose levels with MNR treatment as compared to controls. MNR + IGF1 male fetuses that received either direct or indirect nano-based treatment exhibited increased blood glucose levels as compared to the control and MNR groups. Notably, female fetal blood glucose levels in all groups remained the same.
Increased blood cortisol levels were observed in both males and females belonging to the MNR group as compared to controls. Comparatively, reduced blood cortisol levels were reported following nanoparticle-mediated IGF1 treatment.
Maternal cortisol levels increased with MNR but returned to control levels with repeated nanoparticle-mediated IGF1 placental treatment. Sodium and potassium levels remained unchanged between all treated groups.
Conclusions
The current study demonstrates the effectiveness of the novel nanoparticle-mediated IGF1 gene therapy in restoring fetal growth using a guinea pig model. Based on these positive results, scientists are currently assessing the effectiveness, dosage, and safety of this therapy in non-human primate models.
Journal reference:
Davenport, B. N., Wilson, R. L., Williams, A. A., & Jones, H. N. (2024) Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model. Gene Therapy; 1-11. doi:10.1038/s41434-024-00508-3