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R399E, a mutated form of Growth and Differentiation Factor 5, for disease modification of osteoarthritis.

OBJECTIVE
To preclinically characterize a mutant form of growth and differentiation factor 5 (GDF5, R399E) with reduced osteogenic properties, as a potential disease-modifying osteoarthritis (OA) drug.


METHODS
Cartilage, synovium and meniscus from patients with OA were used to evaluate anabolic and anti-inflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intra-articular (IA) R399E doses were administered bi-weekly 6 times and static incapacitance was determined to assess joint pain. OA was evaluated 13 weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in-life, and OA was assessed after 13 weeks.


RESULTS
Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in chondrocyte 3D cultures. R399E also inhibited the release of interleukin (IL)-1β, IL-6 and prostaglandin E2 (PGE2) from cartilage with synovium, meniscal cell and synoviocyte cultures. In rabbits, mean difference (95% confidence interval (CI)) in weight bearing for R399E vs. vehicle was -5.8 (-9.54, -2.15), -7.2 (-10.93, -3.54) and -7.7 (-11.49, -3.84) for 0.6, 6 and 60 μg doses 6 hours after first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6 μg dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA.


CONCLUSION
R399E influences several pathological processes contributing to OA, highlighting its potential as a disease-modifying therapy.