FEB 22, 2018 10:30 AM PST

Protective Effect of a Novel Noncompetitive IL-1 Receptor-Biased Ligand in an Infection - and Inflammation-Induced Preterm Birth as Well as in Fetal Injury and Developmental Outcomes

Presented at: Drug Discovery 2018
Speaker
  • Professor of Pediatrics, Ophthalmology, Optometry and Pharmacology, Université de Montréal, Adjunct Professor of Pharmacology, McGill University, Université de Montréal
    Biography
      Sylvain Chemtob is a reputed neonatal pharmacologist and physiologist, with expertise on mechanisms implicated in ischemic retinopathies and other conditions involving inflammation including preterm labor. He has also initiated a new technology to develop peptidomimetic drugs that target membrane receptors; some compounds are licensed to industry, and one which successfully completed Phase Ib clinical trial is Phase II-ready (PDC Biotech). His seminal work also triggered the approval (EMEA [2004], FDA [2006]) of new therapies for closure of ductus arteriosus, which is now standard of care.
      Sylvain Chemtob is author of over 270 articles reported in major journals, as well as inventor of 10 patents. He has trained so far 46 graduate students and 29 post-graduate fellows (MDs and PhDs). He has received numerous awards and is a member of the Canadian Academy of Health Sciences. He holds a Canada Research Chair (Vision Science) and the Leopoldine Wolfe Chair in Translational Research in age-related macular degeneration at Universite de Montreal.

    Abstract

    Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. Both preterm labor and neonatal injuries have been linked to inflammation. Of all mediators of inflammation, the major pro-inflammatory cytokine IL-1ß has been shown to trigger a specific pattern of gene expression in uterus and placenta resulting in PTB and in neonatal organ injury and significant fetal demise. Here, we show that a small peptide noncompetitive IL-1R antagonist (rytvela, labeled 101.10) designed and characterized by us, exerts potential therapeutic efficacy in preventing PTB and improving neonatal outcome. Effects of 101.10 were compared to a clinically available IL-1R competitive antagonist (Kineret). Our results show that 101.10 selectively inhibits the downstream stress-associated factors JNK, p38 and c-jun and the small GTPase Rho in myometrial smooth muscle cells and uterine explants and desirably does not interfere with the transcription factor NF-kB activity. Administration of 101.10 to pregnant mice revealed efficacy in preventing IL-1ß-, LTA- and LPS-induced PTB by down-regulating a series of proinflammatory mediators in uterus, placenta, fetal membranes, maternal circulating white blood cells and amniotic fluids. In pregnant mice treated with IL-1ß, 101.10 increased neonatal survival, and this was associated later in life with improved tissue (lung, intestine and brain) analyzed by histology. Specifically, 101.10 protected against IL-1ß-induced cerebral microvascular degeneration, loss in brain mass, which resulted in improved amplitude and latency of visual evoked potential, suggesting normalized brain function reflected in preservation of synaptic transmission through the brain of pups. In LPS-induced PTB (which mimic a gram – infection during pregnancy), 101.10 also increased neonatal survival in addition to decreasing the expression of proinflammatory mRNA transcripts in brain. 101.10 conveyed superior or comparable efficacy to Kineret in all assays performed; Kineret was largely ineffective at prolonging preterm gestation or improving neonatal outcomes, as already reported by other groups. In summary, our data describe a new potential therapeutic candidate that selectively modulates IL-1R-related signaling (thereby preserving NF-?B activity) which is effective in preventing the onset of PTB and associated adverse neonatal outcomes.


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