Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-22
2004-02-10
Kemmerer, Elizabeth (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S004300, C424S085100
Reexamination Certificate
active
06689747
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the repair of cartilage and the treatment of cartilagenous disorders.
BACKGROUND OF THE INVENTION
Cartilagenous disorders broadly describe a collection of diseases characterized by degeneration of or metabolic abnormalities in the connective tissues which are manifested by pain, stiffness and limitation of motion of the affected body parts. The origin of these disorders can be pathological or as a result of trauma or injury.
Osteoarthritis (OA), also known as osteoarthrosis or degenerative joint disease, is the result of a series of localized degenerative processes that affect the articular structure and result in pain and diminished function. The incidence of OA increases with age, and evidence of OA can be detected at least one joint in the majority of the population by age 65. OA is often accompanied by a local inflammatory component that may accelerate joint destruction.
OA is characterized by disruption of the smooth articulating surface of cartilage, with early loss of proteoglycans (PG) and collagens, followed by formation of clefts and fibrillation, and ultimately by full-thickness loss of cartilage. Coincident with the cartilagenous changes are alterations in periarticular bone. The subchondral bone thickens and is slowly exposed. Bony nodules or osteophytes also often form at the periphery of the cartilage surface and occasionally grow over the adjacent eroded areas. OA symptoms include local pain at the affected joints, especially after use. With disease progression, symptoms may progress to a continuous aching sensation, local discomfort and cosmetic alterations such as deformity of the affected joint.
In contrast to the localized nature of OA, rheumatoid arthritis (RA) is a systemic, inflammatory disease which likely begins in the synovium, the tissues surrounding the joint space. The prevalence of RA is about ⅙ that of OA in the general population of the United States. RA is a chronic autoimmune disorder characterized by symmetrical synovitis of the joint and typically affects small and large diarthrodial joints, leading to their progressive destruction. As the disease progresses, the symptoms of RA may also include fever, weight loss, thinning of the skin, multiorgan involvement, scleritis, corneal ulcers, the formation of subcutaneous or subperiosteal nodules and premature death. While the cause of RA and OA are distinctly different, the cytokines and enzymes involved in cartilage destruction appear to be similar.
Because mature chondrocytes have little potential for replication, and since recruitment of other cell types is limited by the avascular nature of cartilage, mature cartilage has limited ability to repair itself. For this reason, transplantation of cartilage tissue or isolated chondrocytes into defective joints has been used therapeutically. However, tissue transplants from donors run the risk of graft rejection as well as possible transmission of infectious diseases. Although these risks can be minimized by using the patient's own tissue or cells, this procedure requires further surgery, creation of a new lesion in the patient's cartilage, and expensive culturing and growing of patient-specific cells. Better healing is achieved if the subchondral bone is penetrated, either by injury/disease or surgically, because the penetration into the vaculature allows recruitment and proliferation of undifferentiated cells to effect repair. Unfortunately, the biochemical and mechanical properties of this newly formed fibrocartilage differ from those of normal hyaline cartilage, resulting in inadequate or altered function. Fibrocartilage does not have the same durability and may not adhere correctly to the surrounding hyaline cartilage. For this reason, the newly synthesized fibrocartilage may be more prone to breakdown and loss than the original articular hyaline cartilage tissue.
Peptide growth factors are very significant regulators of cartilage growth and cartilage cell (chondrocyte) behavior (i.e., differentiation, migration, division, and matrix synthesis or breakdown) F. S. Chen et al.,
Am J. Orthop
. 26: 396-406 (1997). Growth factors that have been previously proposed to stimulate cartilage repair include insulin-like growth factor (IGF-1), Osborn,
J. Orthop. Res
. 7: 35-42 (1989); Florini & Roberts,
J. Gerontol
. 35: 23-30 (1980); basic fibroblast growth factor (bFGF), Toolan et al.,
J. Biomec. Mat. Res
. 41: 244-50 (1998); Sah et al.,
Arch. Biochem. Biophys
. 308: 137-47 (1994); bone morphogenetic protein (BMP), Sato & Urist,
Clin. Orthop. Relat. Res
. 183: 180-87 (1984); Chin et al.,
Arthritis Rheum
. 34: 314-24 (1991) and transforming growth factor beta (TGF-&bgr;), Hill & Logan,
Prog. Growth Fac. Res
. 4: 45-68 (1992); Guerne et al.,
J. Cell Physiol
. 158: 476-84 (1994); Van der Kraan et al.,
Ann. Rheum. Dis
. 51: 643-47 (1992). Treatment with peptide growth factors alone, or as part of an engineered device for implantation, could in theory be used to promote in vivo repair of damaged cartilage or to promote expansion of cells ex vivo prior to transplantation. However, because of their relatively small size, growth factors are rapidly absorbed and/or degraded, thus creating a great therapeutic challenge in trying to make them available to cells in vivo in sufficient quantity and for sufficient duration.
The present invention proposes to overcome this limitation by delivery of a growth factor with a vehicle, and/or as a slow-release formulation. The ideal delivery vehicle is biocompatible, resorbable, has the appropriate mechanical properties, and results in no harmful degradation products.
Another method of stimulating cartilage repair is to inhibit the activity of molecules which induce cartilage destruction and/or inhibit matrix synthesis. One such molecule is the cytokineIL-1&agr;, which has detrimental effects on several tissues within the joint, including the generation of synovial inflammation and up-regulation of matrix metalloproteinases and prostaglandin expression. V. Baragi, et al.,
J. Clin. Invest
. 96: 2454-60 (1995); V. M. Baragi et al.,
Osteoarthritis Cartilage
5: 275-82 (1997); C. H. Evans et al.,
J. Leukoc. Biol
. 64: 55-61 (1998); C. H Evans and P. D. Robbins,
J. Rheumatol
. 24: 2061-63 (1997); R. Kang et al.,
Biochem. Soc. Trans
. 25: 533-37 (1997); R. Kang et al.,
Osteoarthritis Cartilage
5: 139-43 (1997). One means of antagonizing IL-1&agr; is through treatment with soluble IL-1 receptor antagonist (IL-1ra), a naturally occurring protein that prevents IL-1 from binding to its receptor, thereby inhibiting both direct and indirect effects of IL-1 on cartilage. Other cytokines, such as IL-1&bgr;, tumor necrosis factor alpha (TNF-&agr;), interferon gamma (IFN-&ggr;), IL-6 and IL-8 have been linked to increased activation of synovial fibroblast-like cells, chondrocytes and/or macrophages. The inhibition of these cytokines may be of therapeutic benefit in preventing inflammation and cartilage destruction. In fact, molecules which inhibit TNF-&agr; activity have been shown to have potent beneficial effects on the joints of patients with rheumatoid arthritis.
Nitric oxide also likely plays a substantial role in destruction of cartilage. [Ashok et al.,
Curr. Opin. Rheum
. 10: 263-268 (1998)]. Unlike normal joint tissue which does not produce NO unless stimulated with cytokines such as IL-1, synovial membranes or cartilage obtained from arthritic joints spontaneously produce large amounts of nitric oxide for up to 3 days after removal from the joint. In addition, increased concentrations of nitrites are found in synovial fluid of arthritic patients. In addition to its direct stimulation of cartilage catabolism, nitric oxide present in an inflamed joint would likely lead to increased vasodilation and permeability, further release of cytokines such as TNF-&agr; and IL-1 from leukocytes, and stimulation of angiogenesis. Evidence for a causative role of NO in arthritis, comes from animal models where inhibition of NO has been shown
Filvaroff Ellen H.
Okumu Franklin W.
Genentech Inc.
Jiang Dong
Kemmerer Elizabeth
Svoboda Craig G.
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