A revolutionary gene therapy, which has been decades in the making with a focus on the placenta, has shown significant promise in animal studies in the fight against a leading cause of stillbirth and premature birth. A recent Gene Therapy study delved into the effectiveness of a placental nano-based insulin-like 1 growth factor (IGF1) gene therapy to address fetal growth restriction (FGR).
Around 10% of human newborns are either premature or of low birth weight, contributing to over 2.5 million stillbirths and 15 million preterm deliveries. The surviving infants with FGR face a heightened risk of various complications and comorbidities related to the developmental origins of health and disease (DOHaD). These can manifest as cognitive deficits, cardiovascular issues, and obesity in both children and adults.
Currently, there are no available treatments for FGR or conditions like placental insufficiency, where the placenta fails to supply adequate nutrients and oxygen for proper fetal growth. Despite advancements in neonatal care, the focus has mainly been on attaining a normal gestational period for optimal growth.
The intrinsic idiopathic causes of FGR include placental malformation or fetal genetic abnormalities. Extrinsic factors can involve maternal stress or comorbidities such as malnutrition, diabetes, or drug/alcohol use.
Since the placenta serves as the crucial connection between the fetus and the mother, it presents an ideal therapeutic target for treating FGR. Correcting the factors associated with FGR could potentially reduce the number of premature and stillborn infants, as well as adult comorbidities. Human FGR cases have been linked to a downregulation of IGF1, and previous research has established that the IGF signaling axis is a key regulator of placental development and an essential hormone throughout gestation.
The current research explored the capacity of a biodegradable nano-based system to deliver a plasmid containing the IGF1 gene into the placental trophoblast to rectify FGR and placental insufficiency. The nano-based system was crafted by combining a non-viral co-polymer with plasmids housing the IGF1 gene under the control of CYP19A1, a trophoblast-specific promoter.
A guinea pig model of FGR was employed to gauge the efficacy of nanoparticle-mediated IGF1 gene therapy in enhancing fetal growth. The study determined the effectiveness of repeated nanoparticle-mediated IGF1 treatments in restoring abnormal placental physiology and function, which could potentially correct FGR.
Guinea pigs were sorted into different treatment groups, namely control, maternal nutrient restriction (MNR) diet, and MNR + IGF1 groups. After a two-week acclimation and appropriate diet plan, female guinea pigs were anesthetized, and either the nanoparticle or sham treatment was administered to the placenta via ultrasound-guided intra-placental injection. This treatment was repeated every eight days starting from gestation day (GD) 36.
Female and male littermates were also indirectly exposed to the circulating nanoparticles. The dams were sacrificed on GD 60, and the placenta, subplacenta, and decidua were collected for further analysis.
Repeated nanoparticle-mediated IGF1 treatments from mid-pregnancy to near-term did not result in any adverse health complications, placental hemorrhage, or fetal loss. There was no difference in the average litter size between the control and MNR diet groups. Most dams became pregnant during the first mating attempt, while the remaining conceived on the second.
The repeated nanoparticle treatments with the human IGF1 gene induced human IGF1 (hIGF1) messenger ribonucleic acid (mRNA) expression in both the directly injected and indirectly exposed placentas. This expression was absent in the control group that received the sham treatment. A quantitative polymerase chain reaction (qPCR) assay showed that the indirectly exposed placentas had lower hIGF1 expression than the directly injected ones.
Compared to controls, the MNR placentas in males had reduced endogenous levels of guinea pig Igf1 (gpIgf1). However, no significant difference in endogenous gpIgf1 was noted between the MNR + IGF1 placentas and controls.
Sexually dimorphic changes were observed in Igf2, Igf1 receptor (Igf1R), and Igf binding protein 3 (IgfBP3). Although indirect nanoparticle-mediated IGF1 exposure did not seem to affect Igf2 expression, direct IGF1 treatment in the male placenta led to a significant increase in Igf2 expression.
The fetuses whose placentas received repeated nanoparticle-mediated IGF1 injection were heavier than the MNR and control males. A significant correlation between hIGF1 levels in the placenta and male fetal weight was identified.
Blood analysis revealed that male fetal blood glucose levels were lower with MNR treatment compared to controls. The MNR + IGF1 male fetuses that received either direct or indirect nano-based treatment had increased blood glucose levels compared to the control and MNR groups. Notably, female fetal blood glucose levels remained the same across all groups.
Increased blood cortisol levels were seen in both male and female guinea pigs in the MNR group compared to controls. In contrast, nanoparticle-mediated IGF1 treatment led to reduced blood cortisol levels.
Maternal cortisol levels increased with MNR but returned to control levels with repeated nanoparticle-mediated IGF1 placental treatment. Sodium and potassium levels remained unchanged among all treated groups.
The current study effectively demonstrated the potential of the novel nanoparticle-mediated IGF1 gene therapy in restoring fetal growth using a guinea pig model. Encouraged by these positive results, scientists are now evaluating the effectiveness, dosage, and safety of this therapy in non-human primate models, bringing hope for a potential breakthrough in preventing stillbirth and premature delivery.
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