ROR2 blockade for cartilage regeneration and pain relief in OA

Concept

Osteoarthritis is due to loss of cartilage in the joints. Without cartilage, patients struggle with walking, climbing stairs and taking a bath. Pain killers help initially, but when the cartilage is destroyed, a joint replacement is the only remedy that can return patients to some degree of independence, but not to full function. Joint replacements have a finite life and revision surgery to replace them is complex, making them sub-optimal especially for the growing number of younger patients with osteoarthritis.

The project team discovered that blocking a specific receptor called ROR2 on the surface of cartilage cells induces cartilage regeneration and sustained pain relief in mice with osteoarthritis. Additionally, it has been shown that this approach also works on human cartilage.

We hope to develop a first-in-kind disease modifying drug that will slow progression or even revert cartilage breakdown and, at the same time, treat pain for patients with osteoarthritis.

Facts and figures

Project lead
F dell'Accio
Queen Mary University of London
fdellaccio@gmail.com
FOREUM research grant: € 599.862
2019–2022

Meet the team

F dell'Accio
Queen Mary University of London
AS Thorup
Queen Mary University London
S Lohmander
University of Lund
JC Bertrand
Otto-von-Guericke-Universität

Objectives

The formulation that we developed is effective with intra-articular injections every 5 days, which is too frequent to be tolerated by patients. We intend to develop ROR2 blockade which can be delivered systemically – for instance with subcutaneous, self-administered injections - or intra-articularly not more often than every 3 months. Such formulations would be amenable to enter clinical practice.

This research also aims to validate ROR2-dependent biomarkers for patient selection and rapid efficacy assessment.

Patient voice

Patients with arthritis have helped identify priorities of the study and have helped the research team to understand what would be acceptable in terms of frequency of injections, thereby effectively setting the goals of the project.

Throughout this project, patients are being consulted. Patient input has included their views upon local injections that would require visits to a doctor versus systemic injections they could take by themselves, balancing the duration of a dose (needing less frequent injections) versus reversibility in case of non-tolerability. This led to important insights, including that patients with polyarthritis have different needs from patients with a single affected joint. Finally, we have discussed with patients their willingness for samples to be taken to assess suitability for a ROR2-blocking treatment, and to monitor effectiveness of the drug engaging with the target throughout a course of treatment.

Interim results

More than 20 siRNA modifications were generated so far which are being tested for efficacy and durability of the effect.
The ROR2 gene was deleted specifically in the joints of mice with osteoarthritis and currently it is being assessed if this intervention has protected them from cartilage breakdown.

Publications

  • Thorup, A.-S. et al. ROR2 blockade as a therapy for osteoarthritis. Science Translational Medicine 12, (2020) DOI: 10.1126/scitranslmed.aax3063
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  • Nalesso, G. et al. Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis. Scientific Reports 11, 5682 (2021) PMCID: PMC7952598 DOI: 10.1038/s41598-021-82067-w
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  • Thorup, A.-S., Dell’Accio, F. & Eldridge, S. E. Lessons from joint development for cartilage repair in the clinic. Dev. Dyn. (2020) doi:10.1002/dvdy.228. DOI: 10.1002/dvdy.228
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  • Eldridge, S. E. et al. Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis. Science Translational Medicine 12, (2020). DOI: 10.1126/scitranslmed.aax9086
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EULAR Abstracts

2021

OPO200: Blocking ROR2 improves cartilage integrity and provides pain relief in osteoarthritis

Goals/Milestones

  • Aim 1: Generate and validate a humanized monoclonal blocking antibody to ROR2
  • Aim 2: Stabilize siRNA for longer-term delivery
  • Aim 3: Identify biomarkers for patient selection and assessment of efficacy