Preterm birth (PTB) affects more than 10% of pregnancies worldwide and is the leading cause of neonatal mortality. Current treatments target myometrial contractility and are largely ineffective at improving perinatal outcomes. Myometrial contractions represent the final stage of a long process of uterine activation orchestrated by in utero inflammatory processes. If triggered prematurely (e.g. by infection), inflammation inevitably leads to preterm labor, with the timing of onset being inversely correlated with adverse neonatal outcomes and associated lifelong complications. Interleukin-1 (IL-1) is a major proinflammatory cytokine that has been firmly linked to human PTB and fetal organ injuries.
In a review article published in Current Pharmaceutical Design, Nadeau-Vallée et al. summarize the most recent evidence on the efficacy of molecules that target IL-1 to prevent PTB. Of all inhibitors of IL-1, the selective IL-1 receptor inhibitor rytvela (all-d heptapeptide) stands out preclinically as superiorly potent, effective, and safe in the prevention of PTB and its consequences. "Rytvela exerts benefits in decreasing uteroplacental inflammation, decreasing premature birth, prolonging gestation, increasing fetal survival, and improving fetal and neonatal outcome including that of the neurodevelopment" says Dr. Sylvain Chemtob, neonatologist, researcher, and principal author of the article. "Other than preventing preterm labor, rytvela also decreases inflammation inside the fetal compartment and in fetal organs, which is of significant importance because numerous neonatal conditions have been linked to inflammation independent of prematurity. Antenatal treatment with rytvela results in normalisation of lung, intestine and cerebral pathology scores during development and at adulthood".
The effects of rytvela have been validated in vitro in murine and human uterine and immune cells, and in vivo in numerous murine models of PTB. Mechanistically, rytvela binds on a site remote from the binding site of IL-1 and act as a biased ligand by selectively inhibiting the p38/JNK/AP-1 pathway while preserving the activity of transcription factor NF-kB. This innovative mechanism of action may help decrease adverse effects (e.g. immunosuppression) which are particularly undesirable in the context of pregnancy.
Nadeau-Vallee M, Obari D, Beaudry-Richard A, Sierra EM, Beaulac A, Maurice N, Olson DM, Chemtob S. Preterm Birth and Neonatal Injuries: Importance of Interleukin-1 and Potential of Interleukin-1 Receptor Antagonists. Curr Pharm Des. 2017;23(40):6132-6141.
Gross effect of antenatal treatment with 101.10 compared to saline in 2 newborn mice (same adjusted age) in an inflammatory model of preterm birth. Note macroscopic delay in hair development and global growth in the saline-treated neonate.
Source: Dr. Sylvain Chemtob, CHU Sainte-Justine, Montreal, QC Canada
