Progression of osteoarthritis (OA) can be characterized by catabolic changes in the composition and structure of the extracellular matrix (ECM), which triggers inflammation and limits self-renewal of damaged cartilage
Natural, healthy cartilage-matrix is mainly composed of collagen type II which provides tensile support for the tissue. Aggrecan, a water-attracting, negatively charged proteoglycan provides the compression-resistance and shock absorbing properties of cartilage under loading.
Although disease initiation may be multi-factorial in OA, it is characterized by sequential events that affect the integrity of ECM; aggrecan content is decreased, while collagen content is increased. This change in ECM composition predisposes the tissue for mechanical fault, resulting in significantly altered mechanical properties, followed by breakdown of cartilage and underlying bone.
On the molecular level, OA progression can be characterized as uncontrolled proteolytic extracellular matrix destruction. Aggrecanase-mediated aggrecan degradation is a significant event in early stage OA leading to dramatic changes of the environment of residing cartilage forming cells. Matrix degradation products trigger chondrocytes to become more hypertrophic, characterized by the secretion of inflammatory cytokines and critical proteases instead of cartilage-anabolic proteins. In addition, the chondrogenic differentiation of mesenchymal stem cells (MSCs) is also negatively affected, which further limits the intrinsic regeneration capacity of the tissue.
Overall, the interplay between changes in ECM and changes in cellular function under inflammation forms a positive feedback loop that drives the pathology of OA.
Thus, an effective disease-modifying treatment for patients with established OA requires a dual therapeutic approach. While progressive proteolytic matrix destruction needs to be inhibited, the regenerative capacity of affected cartilage requires effective stimulation.
Unique dual mode of action selectively blocks ECM degradation in OA cartilage and restores regeneration capacity of cartilage-forming cells.
BN-02 works anti-catabolic and pro-anabolic.
BN-02 represents an optimized recombinant variant of a natural cartilage rescue and repair factor which is characterized by its unique capability to reverse major disease driving processes in OA simultaneously.
The unique dual mode of action of BN-02 to block ECM degradation while restoring the regenerative capacity of damaged cartilage provides the potential to change the standard of care for OA.
Cartilage-specific and selective binding of BN-02 to its different targets represents the molecular basis for its multimodal functionality:
Anti-catabolic effect by protecting cartilage proteoglycan from cleavage by proteases:
Selective cartilage specific effect on ADAMTS-4/5 and MMP protease activity
Reduction of pro-inflammatory cytokines and inflammation
Effect on nociceptive neurons for pain reduction
Pro-anabolic effect by inducing an anabolic cascade in OA cartilage:
Induction of Regulators of chondrogenesis in cartilage forming cells
Increase production of cartilage matrix proteins