Osteoarthosis/osteoarthritis (OA) is a seriously disabling condition characterised by a progressive erosion of joint cartilage due to degradation of the joint matrix and loss of the main cell components: chondrocytes.
The exact etiology of the condition is still unclear. However, recent studies have shown it may be triggered by mechanical imbalance affecting the whole joint. Mechanical joint instability may be caused by various factors (e.g. trauma and/or mechanical stress involving the joint capsule in toto, inflammation of the joint system) and may upset the delicate balance between synthesis and degradation of the extracellular matrix, which is mainly synthesised by chondrocytes and synoviocytes.
When this perfect, but fragile, homeostasis is upset, degradation of the matrix is uncompensated by its synthesis because of the loss of chondrocytes, and gradually worsens.
Indeed, excessive and/or incorrect loading of the joint may cause a chondrocyte response that manifests itself in synthesis of the very enzymes responsible for degradation of the cartilage, protease enzymes called metallo-proteinase (MMP). These are synthesised by the chondrocytes when stimulated by inflammatory cytokines, such as IL-1 and TNF-α, that are produced and released in the joint cavity, particularly at the onset of an inflammatory pathology. IL-1 also stimulates synthesis of high levels of nitric oxide (responsible for chondrocyte death by apoptosis) as well as inhibiting proteoglycan synthesis (matrix components) by the chondrocytes themselves (Dozin B. et al., Matrix Biology, 2002, 21:449-459).
It is known that the extracellular matrix must be integral for chondrocytes to survive. Data in the scientific literature have demonstrated that degradation of molecules from the matrix may lead to the release of other molecules (that likewise derive from degradation of the matrix) similarly capable of inducing chondrocyte apoptosis (Cao L. et al., Exp Cell Res, 1999, 246:527-537).
For this reason, the cartilage of osteoarthrotic patients presents a decrease in cellularity and corresponding increase in the formation of empty “lacunae” within the joint matrix.
High levels of IL-1 have been found in the synovial fluid of patients suffering from rheumatoid arthritis (RA) and psoriatic arthritis (Arend W. P. et al., Arthritis Rheum, 1995, 38:151-160).
The physiological aging process of the joint surfaces also seems to involve the enzymatic mechanisms peculiar to OA. Consequently, the therapies normally used to treat this pathology are also applied to joints with cartilage partially or totally damaged by “normal” joint aging.
The cartilage matrix is constituted by a three-dimensional structure formed by molecules of collagen and aggregated proteoglycan complexes. These in turn are constituted by a supporting structure based on hyaluronic acid that interacts with glycosaminoglycan molecules (GAG), non-covalently bound to polypeptide sequences associated with hyaluronic acid (HA), thus giving the cartilage both mechanical and viscoelastic properties.
Indeed, HA is a molecule with special viscoelastic properties, synthesised and secreted also in the joint cavity mainly by the synoviocytes (Asari A. et al., Arch Histol Cytol, 1995, 58(1):65-76) and it is therefore one of the main components of synovial fluid. When the joint is moved slowly, HA acts as a viscous lubricant, while when it is moved briskly HA's elastic properties enable it to act as a shock absorber counteracting any trauma or microtrauma to which the joint may be exposed.
It is known that the functional characteristics of the synovial fluid depend on both the concentration and degree of polymerisation of HA, and that any changes in these may lead to OA-type histological damage to the joint.
The turnover of HA (and of glycosaminoglycans in general) in healthy synovial fluid is usually rapid (1 day in the sheep), but in the course of OA, a drop in its concentration (associated with a decrease in GAG) and its mean molecular weight (MW) has been observed, as well as a marked decrease in its turnover (Balazs E A. et al., J Rheumatol Suppl, 1993, 12:75-82; Belcher C. et al., Annals of the Rheumathic Disease, 1997, 56:299-307).
Further findings have shown that HA not only has biomechanical viscosupplementation properties, but also the ability to protect chondrocytes from the action of IL-1, measured as the percentage of proteoglycan synthesis (Brun P. et al., OsteoArthritis and Cartilage, 2003, 11:208-216), (Stove J. et al., Journal of Orthopaedic Research, 2002, 20:551-555).
Based on these observations, it was Balazs who first suggested that the evolution of osteoarthrosis might be modified by administering exogenous HA, especially high-molecular-weight HA, directly into the joint cavity.
There are various drugs currently on the market for the intra-articular administration of HA in OA, such as: Hyalgan®, HA purified from rooster combs with a MW of: 5-7.5×105 Da (European patent No. 0138572 B1); Synvisc®, (Hylan G-F 20) HA cross-linked with formaldehyde and divinyl sulphone with a MW of: 6-7×106 Da (U.S. Pat. No. 4,713,448), Artz®, HA with MW: 6.2-12×105 Da.
Moreover, European patent No. 1144459 B1 describes and claims a new HA derivative for the treatment of OA joint pathologies. It is a hyaluronic acid derivative cross-linked with polyamines to form amide bonds with the carboxy groups of HA. It is in the form of a generally water insoluble hydrogel, prepared and subsequently tested with a final degree of cross-linking of 50% (Barbucci R. et al., Biomaterials, 2002, 23:4503-4513).
Intra-articular injections of HA are known to provide viscosupplementation and improve function in limbs affected by OA pathology, with a consequent reduction in joint pain. However, HA's residence time in the joint capsule is limited to about 40 hours after application of Hyalgan® (Fraser J R. et al., Seminars in Arthritis and Rheumatism, 1993, 22:9-17) while in the case of Synvisc® it may last for a few days (Fiorentini R., Proceedings of the US FDA Advisory Panel on Orthopaedic and Rehabilitation Devices, Nov. 21, 1996 Fairfax (VA):CASET Associates, 1996; Berkowitz D., Proceedings of the US FDA Advisory Panel on Orthopaedic and Rehabilitation Devices, Nov. 20, 1996 Fairfax (VA):CASET Associates, 1996).
This limitation means that weekly administration cycles are usually called for, with a total of at least 5 intra-articular injections.
Moreover, some of these drugs based on chemically modified HA, such as Synvisc®, have been involved in reports of sometimes serious adverse events (Hammesfahr J F. et al., The American Journal of Orthopaedics, 2003, 32:277-283), probably following the onset of inflammatory processes, especially linked with eosinophil recruitment (Schiavinato A. et al., Clinical and Experimental Rheumatology, 2002, 20:445-454).
Considering the above, new chemical derivatives of HA are being studied that enable the problems linked with both residence time in the joint cavity and the risk of toxicity due to solvents and/or particular chemical agents used in the chemical modification of HA to be overcome, while maintaining all the characteristics and intrinsic properties of the polysaccharide unaltered.
The Applicant has surprisingly discovered that HA, chemically bound to an amine by its carboxy group and called HYADD™ (European patent No. 1095064 B1), has all the intrinsic properties of HA described above, demonstrating, moreover, that it provides a surprising proliferative stimulus towards OA human chondrocytes, elicits a protective action on OA synovia, slowing down the degenerative process, reducing the changes in the morphology of OA cartilage surface and the formation of osteophytes (the bony formations typical of osteoarthrosis), thus representing a new curative therapy for OA and, lastly, that it possesses viscoelastic characteristics that allow the partial and/or complete integration/substitution of the synovial fluid in a joint that has been damaged or treated by surgery, enabling correct, painless loading of the knee.
USPTO Backgrounds
USPTO Backgrounds