OP0200 BLOCKING ROR2 IMPROVES CARTILAGE INTEGRITY AND PROVIDES PAIN RELIEF IN OSTEOARTHRITIS

Background: Osteoarthritis (OA) is the leading cause of chronic disability worldwide, affecting 12% population, and yet we still do not have a disease-modifying treatment. Cartilage breakdown hallmark OA, patients suffer from pain loss joint function/independence, severely quality life. Therefore, there huge unmet clinical need. Receptor tyrosine kinase–like orphan receptor 2 (ROR2) non-canonical WNT that regulates planar cell polarity pathway, controlling limb outgrowth during development. During skeletal development, chondrocytes require ROR2 to undergo hypertrophy throughout process endochondral bone formation 1 . Loss function mutations in humans causes Recessive Robinow Syndrome, shortening brachydactyly 2,3 Although absent healthy adult articular cartilage, our initial studies identified high expression levels with suggesting role disease Objectives: To test potential blockade as treatment for OA. Methods: Human cartilage organoid model nude mice, menisco-ligament injury (MLI) OA behavioural studies, vitro cells. Results: ROR2/WNT5A signaling was increased osteoarthritic cartilage. Blocking sufficient induce chondrogenesis suppress aggrecanases mesenchymal stem line, support human mice using primary In MLI blocking therapeutic regime atelocollagen-conjugated siRNA resulted reduced destruction rapid sustained relief. Due limited pattern adulthood, no systemic or local toxicity were expected, nor any observed 4 With current technology, requires intra-articular (IA) injections conjugated atelocollagen every 5 days. Preliminary efficacy data potentially longer-acting blockers are promising. The mechanism action independent modulation canonical signaling. promoted nuclear localization YAP, which required both Rho G-proteins. YAP downstream also Rho, but TEAD inhibition required, sufficient, chondrogenic effect ROR2. additional, unknown mechanisms must be involved Conclusion: has resulting protection relief murine model. This will crucial success promote patient compliance. Our siRNA-atelocollagen based technology IA too frequently acceptable patients. We developing can administered systemically more often than 3 months - work funded by FOREUM. References: [1]DeChiara, T. M. et al. Ror2, encoding receptor-like kinase, growth plate Nat. Genet. 24 , 271–4 (2000). [2]Bokhoven, H. Van, Celli, J. & Kayserili, Mutation gene kinase autosomal recessive syndrome. Nature 25 423–426 [3]Afzal, A., Rajab, Fenske, C. Oldridge, syndrome, allelic dominant type B, caused mutation 419–422 [4]Thorup, A.-S. therapy osteoarthritis. Sci. Transl. Med. 12 eaax3063 (2020). Acknowledgements: gratefully acknowledge funding this Medical College St Bartholomew’s Hospital Trust, William Harvey Research Foundation, FOREUM foundation research rheumatology (1016807), MRC (MR/L022893/1, MR/N010973/1, MR/P026362/1, MR/K013076/1), Versus Arthritis (21515, 20886, 21621, 20859), DFG Emmy-Noether program (BE4328/5-1). Disclosure Interests: Anne-Sophie Thorup: None declared, Danielle Strachan: Sara Caxaria: Blandine Poulet: Bethan Thomas: Suzanne Eldridge: Giovanna Nalesso: James Whiteford: Costantino Pitzalis: Thomas Aigner: Roger Corder: Jessica Bertrand: Francesco Dell’Accio Consultant of: Samumed UCB