Enyx Therapeutics LLC

Anti-eosinophil Gene Therapy for Eosinophilic Esophagitis - Abstract. Eosinophilic Esophagitis (eoe), a Chronic Upper Gastrointestinal Disabling Disorder Affecting Children and Adults, Is Characterized by Eosinophil Esophageal Inflammation, Progressive Disordering of Esophageal Architecture, Esophageal Dysfunction, Dysphagia and Food Impaction. There Are No Approved Therapies for Eoe; Standard of Care Includes Topical or Systemic Glucocorticoids and Diet Modification. Lexeo Therapeutics, an Early Stage Gene Therapy Company, Is Developing a Single Administration Gene Therapy to Treat Eoe With LXI02, a Nonhuman Primate Serotype RH.10 Adeno-associated Virus (AAVRH.10) Vector Administered Intravenously, Designed to Genetically Modify the Liver to Express and Secrete a Monoclonal Antibody Directed Against Eosinophils, Resulting in Clearance of Eosinophils From the Circulation and Tissues. the Advantage of Gene Therapy Over Conventional Monoclonal Therapy Is Persistent Stable Levels of the Anti-eos Monoclonal Following Single Intravenous Therapy. in Collaboration With the Crystal Laboratory, Weill Cornell, a Novel Murine Eoe Model Was Created, Induced by Sensitization to Peanuts, Resulting in Esophageal Eosinophil Accumulation and Concomitant Derangement of Esophageal Architecture. a Single Intravenous Administration of AAVRH.10MANTI-EOS Coding for Anti-siglec-f, a Monoclonal Antibody Directed Against Murine Eosinophil Sialic Acid-binding Immunoglobulin-like Lectin (siglec-f), Induced Murine Eosinophil Apoptosis, Clearance of Blood Hyper Eosinophilia, Reduction in Esophageal Eosinophil Accumulation Reduction in Esophageal Architectural Derangement and Decrease in Food Impaction. as the Next Step in Translating This Therapy to Humans, We Generated LXI02 (AAVRH.10HANTI-EOS), Identical to AAVRH.10MANTI-EOS, But With the Coding Sequence for ANTI-SIGLEC-8, an IGG1 Human Ortholog of Murine Siglec-f. the Focus of This Phase I STTR, Is to Demonstrate That LXI02 Is Effective as an Anti-human Eosinophil Therapy. We Will Administer LXI02 Intravenously to Immunodeficient Mice at Varying Doses and Assess Over Time Liver Expression and Blood Levels of Anti- SIGLEC-8 and That the Expressed ANTI-SIGLEC-8 Will: Bind to SIGLEC-8 and to Human Eosinophils; Mediate Natural Killer Cell Antibody-dependent Cytotoxicity and Apoptosis of Human Eosinophils; Enhance Clearance of Human Eosinophils in Immunodeficient Mice; and Demonstrate That LXI02 Gene Expression Can Be Shut Off If Required. With Success of This Phase I STTR, Lexeo Will Apply for a Phase 2 STTR, With the Goal to Translate LXI02 to Human Therapy for Eoe. Aim 1. to Demonstrate That LXI02 Will Mediate in Immunodeficient Mice Persistent, Steady State Levels of ANTI-SIGLEC-8 That Functions Effectively to Reduce Levels of Human Eosinophils. Aim 2. to Show That Administration of Galnac Conjugated Sirna Cognate to a Sequence in LXI02 Will Suppress Expression of the ANTI-SIGLEC8 Antibody Coded by LXI02.