Methods to Improve Maternal-Fetal Tolerance and Pregnancy Success through AhR Receptor Modulation

Background & Unmet Need

• Immune tolerance at the maternal-fetal interface (MFI) is required for fetal development, with dysregulation leading common pregnancy complications such as miscarriage or pre-term birth
• Maternal interferon gamma (IFNɣ) and interleukin-17 (IL-17) are normally protective during pregnancy, but high amounts are linked to adverse outcomes
• Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Treg) have been suggested to reduce inflammation during pregnancy
• Analysis of autoimmune conditions and associated pregnancy complications supports the conclusion that rampant inflammation lowers maternal-fetal tolerance
• Unmet Need: Therapies to regulate unchecked inflammation are needed to prevent pregnancy complications and improve maternal-fetal tolerance

Technology Overview

• The Technology: A therapeutic approach to improve maternal-fetal immune tolerance through aryl hydrocarbon receptor (AhR) activation by tryptophan metabolite supplementation
• The Discovery: Rates of fetal resorption in mice were higher in germ-free (GF) versus specific pathogen free (SPF) mice
• Gram-positive bacteria that release tryptophan (e.g. Lactobacillus murinus) increase MDSC and Treg activity, reducing IFN and IL-17 responses at the MFI to decrease incidence of complications via immunosuppression and downregulation of IFNɣ
• PoC Data: Administration of indole-3-carbinol as a proxy for tryptophan led to ~ less fetal resorption in germ-free (GF) mice
• Monocolonization with tryptophan-metabolizing Lactobacillus murinus reduced fetal resorption and restored immune tolerance markers compared to non-metabolizing bacteria or germ-free controls

Technology Applications

• Therapeutic intervention for high-risk patients with dysregulated maternal-fetal immune tolerance
• Preventative supplementation to maintain healthy maternal-fetal interface tolerance throughout pregnancy

Technology Advantages

• May be formulated either as a small molecule or probiotic
• Utilizes naturally occurring compounds and safe bacterial strains, enabling faster regulatory approval pathways