A recent gene therapy study has investigated the use of placental nano-based insulin-like growth factor 1 (IGF1) gene therapy to address fetal growth restriction (FGR), a condition associated with stillbirth and preterm delivery. This innovative therapy aims to correct placental insufficiency, which is a primary cause of FGR, by delivering the IGF1 gene directly to the placenta using a biodegradable nano-based system.
FGR is a significant global health issue, affecting approximately 10% of human newborns, contributing to over 2.5 million stillbirths and 15 million preterm births annually. FGR neonates face an increased risk of developmental complications, including cognitive deficits, cardiovascular disease, and obesity. The condition results from either intrinsic causes, such as placental malformation or fetal genetic abnormalities, or extrinsic factors, including maternal stress, malnutrition, diabetes, and drug or alcohol use.
The placenta plays a crucial role in facilitating fetal growth by transferring essential nutrients and oxygen from the mother. Therefore, it has become a key target for therapies aimed at reducing FGR, stillbirth, and preterm deliveries.
Human cases of FGR are often associated with the downregulation of IGF1, a crucial hormone that regulates placental development and supports the entire gestation period. Previous studies have highlighted the importance of the IGF signaling axis in ensuring healthy fetal growth, and correcting its dysfunction could offer a potential solution to prevent FGR.
The study aimed to investigate the use of a nano-based system for delivering the IGF1 gene to the placental trophoblast cells. The system involves complexing a non-viral co-polymer with plasmids containing the IGF1 gene, regulated by a trophoblast-specific promoter (CYP19A1). This delivery method is designed to target the placenta directly, where it can correct FGR and placental insufficiency.
To evaluate the therapy’s effectiveness, researchers used a guinea pig model of FGR. Female guinea pigs were divided into several groups: control, maternal nutrient restriction (MNR) diet, and MNR + IGF1 groups. The guinea pigs were treated with nanoparticle-mediated IGF1 gene therapy via ultrasound-guided intra-placental injections, repeated every eight days starting from gestation day 36.
The study found that repeated nanoparticle-mediated IGF1 treatments from mid-pregnancy to near-term did not cause any adverse health effects, placental hemorrhage, or fetal loss. There was no significant difference in average litter size between the control and MNR diet groups. Importantly, most female guinea pigs became pregnant during the first mating attempt, and the remaining ones became pregnant after the second attempt.
The treatment successfully induced human IGF1 (hIGF1) expression in the placenta, both directly and indirectly. However, the hIGF1 expression was lower in the indirectly exposed placentas compared to those directly injected with the nanoparticles.
A significant reduction in guinea pig Igf1 (gpIgf1) levels was observed in MNR placentas compared to controls, though no such difference was found in MNR + IGF1 treated placentas. Sexually dimorphic changes were also noted in the expression of Igf2, Igf1 receptors (Igf1R), and Igf binding proteins (IgfBP3), particularly in male placentas where direct IGF1 treatment led to a significant increase in Igf2 expression.
Fetuses whose placentas received repeated nanoparticle-mediated IGF1 injections exhibited increased weight compared to those in the MNR and control groups, with a notable association between IGF1 levels in the placenta and male fetal weight.
Blood analysis revealed that male fetuses in the MNR group had reduced blood glucose levels, while those receiving the MNR + IGF1 treatment showed increased blood glucose levels, aligning with the control group. Interestingly, blood glucose levels in female fetuses did not differ across the groups.
Both male and female fetuses in the MNR group exhibited elevated blood cortisol levels compared to controls. However, the nanoparticle-mediated IGF1 treatment effectively reduced cortisol levels in both sexes, indicating a potential for stress reduction with this therapy.
Maternal cortisol levels also increased with the MNR diet but returned to normal levels after repeated nanoparticle-mediated IGF1 treatment. Sodium and potassium levels remained unchanged across all groups, suggesting that the therapy did not have significant adverse effects on electrolyte balance.
The study demonstrates the potential of nanoparticle-mediated IGF1 gene therapy in improving fetal growth and restoring placental function in the context of FGR. These promising results in the guinea pig model suggest that this gene therapy could be a novel approach for preventing stillbirths and premature deliveries.
Researchers are now moving forward with further investigations into the effectiveness, optimal dosage, and safety of this therapy in non-human primate models. If successful, this therapy could revolutionize the treatment of FGR and placental insufficiency, offering new hope for at-risk pregnancies and improving outcomes for both mothers and their babies.
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