WNT Scientific LLC

Small Molecules Promote Tendon Regeneration by Targeting Endogenous Stem Cells - Abstract Tendon and Ligament Injuries Represent an Acute Healthcare Burden in the United States, Costing >$30 Billion Annually. Tendon Injuries Frequently Result in Scar-like Tissue With Inferior Physical Properties - However No Regenerative Therapy Exists to Date. Recently, We Have Identified and Characterized Perivascular (CD146+) Tendon Stem/progenitor Cells (TSCS) That Play an Essential Role in Tendon Healing via Fak and ERK1/2 Signaling. in Our Preliminary Study, We Screened Small Molecules From a Library of Fak and ERK1/2 Agonists and Identified Oxotremorine M (oxo-m) and PPBP Maleate (4-PPBP) That Stimulated TSCS Toward Regenerative Tendon Healing. Oxo-m and 4-PPBP Were Originally Developed for Treating Neuronal Diseases But Have Never Been Tested in the Musculoskeletal System. in Vitro, a Combination of Oxo-m and 4-PPBP Induced Significant Increases in the Expression of Tendon-related Genes Involved in Tendon Repair. Oxo-m and 4-PPBP Showed No Cytotoxicity Up to 10X Working Doses. Western Blot and Sirna Knockdown (KD) Confirmed That Fak and ERK1/2 Signaling Regulate Oxo -M & 4-PPBP-INDUCED Tenogenic Differentiation of TSCS. in Vivo, Direct Topical Delivery of Oxo-m and 4-PPBP Onto Full-transected Rat Patellar Tendons (PT) Significantly Improved Tendon Healing, as Observed Histologically as Densely Reorganized Collagen Fibrils, and Functionally as Significantly Enhanced Tensile Strength. This Process Was Guided by a Rapid But Transient Increase in the Number Endogenous TSCS Undergoing Tenogenic Differentiation. in Addition, Oxo-m and 4-PPBP Specifically Targeted CD146+ TSCS Through Muscarinic Acetylcholine Receptors (ACHRS) and S1 Receptor (S1R) Pathways, With Minimal Effect on Other Types of Tendon Cells. These Findings Demonstrate a Novel and Promising Activity of the Combination of Oxo-m and 4-PPBP in Tendon Healing by Specifically Targeting Endogenous TSCS. the Overall Objectives of This STTR Grant Are to Develop a Reliable and Effective Small Molecule-based Regenerative Therapy for Tendon Injuries by Transiently Activating Regenerative Pathways of Endogenous TSCS and Repair Tendon Tears. the Overarching Goal of the STTR Phase I Grant Is to Optimize the Combination of Oxo-m and 4-PPBP, the 2 Compounds and Determine Their Drugability in Combination. the 2 Aims of the Phase I STTR Are to Obtain Robust Proof-of-concept and Preliminary Safety Data to Establish Technical Merit, Feasibility, and Commercial Potential of the Innovative Technology.