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Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury
Jun Lei1, Jason M Rosenzweig1, Manoj K Mishra2
1Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Insights
Low-dose N-acetyl-L-cysteine therapy delivered via dendrimer nanoparticles (DNAC) effectively reduced preterm birth rates in a mouse model. DNAC also improved offspring neurobehavioral outcomes and reduced neuroinflammation, offering a promising therapeutic strategy.
Area of Science:
- Perinatology
- Neuroscience
- Immunology
Background:
- Preterm birth is a leading cause of neurological disabilities in children.
- Current N-acetyl-L-cysteine therapies require high doses with significant side effects.
- Intrauterine inflammation is a key contributor to preterm birth and adverse neurodevelopmental outcomes.
Purpose of the Study:
- To investigate the efficacy of low-dose N-acetyl-L-cysteine delivered via maternal dendrimer nanoparticles (DNAC) in a mouse model of intrauterine inflammation.
- To assess DNAC's impact on preterm birth rates, placental immunity, and offspring neurodevelopmental outcomes.
Main Methods:
- Mice with intrauterine inflammation were treated with intraperitoneal maternal DNAC.
- Preterm birth rates, placental immune cell infiltration (specifically CD8+ T-cells), fetal neuroinflammation, and long-term microglial activation in offspring were analyzed.
Main Results:
- Maternal DNAC administration significantly reduced the rate of preterm birth.
- DNAC altered the placental immune profile, decreasing CD8+ T-cell infiltration.
- Offspring exhibited improved neurobehavioral outcomes, reduced fetal neuroinflammation, and decreased long-term microglial activation.
Conclusions:
- Low-dose DNAC is effective in preventing preterm birth and associated adverse neurological outcomes in a mouse model.
- CD8+ T-cells play a role in the maternal-fetal inflammatory interface.
- DNAC represents a novel therapeutic approach for managing intrauterine inflammation and its consequences.
Abstract:
Preterm birth is a major risk factor for adverse neurological outcomes in ex-preterm children, including motor, cognitive, and behavioral disabilities. N-acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes.
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