Preterm Birth & Fetal Inflammation
We know labour is initiated by an inflammatory event that amplifies exponentially and activates the uterine tissues to facilitate labour and birth. Current therapeutics (tocolytics) to block preterm birth (PTB) focus on stopping contractions. Unfortunately, this is too far down the birth cascade to prolong pregnancy by more than a few days. Therefore, we propose that therapeutics should target the upstream regulators of this inflammatory cascade.
Ongoing intrauterine inflammation also harms the developing fetal organs and can lead to fetal inflammatory response syndrome (FIRS). Babies born with FIRS can suffer many complications that may be fatal or impair their long-term health (for a summary, check Fetal Inflammation). Therefore, PTB therapeutics that block the inflammatory cascade will also decrease the fetus’s exposure to harmful inflammatory molecules.
IL-1β is a potent cytokine activated early in the birth cascade (see Pathway to Preterm Birth). When IL-1β binds to its receptor (IL-1R), it activates nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signal transduction pathways. Kineret, canakinumab, and rilonacept are all FDA-approved therapeutics for inflammatory diseases, and they block IL-1β from binding to IL-1R. However, they are not approved for use in pregnant women because they inhibit IL-1R communication through both signal transduction pathways. This broad inhibition could damage the growing fetus and make the mother vulnerable to infection.
Figure 1: Therapeutic Targeting of IL-1R
Rytvela is a 7 D-amino acid peptide allosteric blocker of IL-1R created by Dr. Sylvain Chemtob. Rytvela selectively inhibits IL-1R signal transduction through the MAPK pathway (Figure 1). By only blocking the MAPK pathway, Rytvela stalls labour while keeping the mother’s innate immune system functional.
We can induce PTB in mice by injecting them with IL-1β, lipoteichoic acid, Poly I:C, or lipopolysaccharide. Co-administration of rytvela eliminates the increased rates of PTB, fetal death, and infiltration of leukocytes into the reproductive tissues and fetal brains. Rytvela also blocked intrauterine inflammation in a sheep model of chorioamnionitis. Therefore, we believe rytvela is a strong therapeutic candidate for stopping both PTB and the accompanying fetal inflammation.
We know IL-6 is a critical player in the inflammatory cascade that leads to birth. Knockout mice for IL-6 experience delayed labour and birth, but it is normalized if they are also treated with IL-6. This cytokine increases in the maternal plasma, the human fetal membranes, and the myometrium and cervix in women nearing labour.
We are now testing the effectiveness of another small peptide allosteric blocker of the IL-6 receptor (HSJ633) developed by Dr. Chemtob that targets the IL-6 receptor in a selective manner (like Rytvela for IL-1β). We are interested in its effectiveness in preventing preterm delivery and stopping fetal inflammation in a mouse model of inflammation.