ROR2 blockade for cartilage regeneration and pain relief in osteoarthritis

We have discovered that ROR2 blockade, using RNAi, induces chondrogenesis resistant to hypertrophy. In therapeutic regime, ROR2 blockade results in reduced cartilage destruction and sustained pain relief in a murine model of osteoarthritis induced by joint destabilization. With our current technology, ROR2 blockade requires intra-articular injections of siRNA conjugated with atelocollagen every 5 days. Frequent intra-articular injections are not acceptable in routine clinical practice. We intend to develop ROR2 blockade which can be administered systemically or intra-articularly not more often than every 3 months, and biomarkers predicting efficacy. In aim 1 we will generate blocking reagents such as a monoclonal antibody or soluble extracellular domain of ROR2. Such reagents will be tested and validated in human chondrocytes in vitro as well as in vivo in murine models of osteoarthritis. In aim 2 we will chemically stabilise siRNA and optimize carrier molecules to achieve efficient ROR2 blockade by systemic injections or persistence in the joint after intra-articular injections lasting at least three months. In aim 3 we will use transcriptional targets of ROR2 signalling as markers predictive of response to ROR2 blockade and /or as surrogate potency markers. Such markers will be useful for patient stratification and rapid outcome assessment.