Project Grant R41AR079360

Award Date 9/5/21
Completion Date 8/31/22
Dollars Obligated $756K
Federal Grant Program
93.846
Assistance Type
Project Grant
Place of Performance
New York, USA
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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.

Posted 9/3/21, 12:00 AM