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  Method and means for treatment of osteoarthritisUSPTO Application #: 20070004658Title: Method and means for treatment of osteoarthritis Abstract: The present invention relates to in vivo and in vitro methods, agents and compound screening assays for inducing anabolic stimulation of chondrocytes, including cartilage formation enhancing pharmaceutical compositions, and the use thereof in treating and/or preventing a disease involving a systemic or local decrease in mean cartilage thickness in a subject. (end of abstract) Agent: Synnestvedt & Lechner, LLP - Philadelphia, PA, US Inventors: Nick Vandeghinste, Peter Herwig Maria Tomme, Frits Michiels, Libin Ma, Blandine Mille-Baker, Helmuth H.G. van Es USPTO Applicaton #: 20070004658 - Class: 514044000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20070004658. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 60/581,568, filed Jun. 21, 2004, the disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention relates to the field of medicinal research, cartilage physiology and diseases involving the degeneration of cartilage tissue. More specifically, the invention relates to methods and means for identifying compounds that stimulate anabolic processes in chondrocytes and that typically induce the synthesis of cartilage. The invention also relates to the compounds that are useful in the treatment of osteoarthritis. [0003] Cartilage is an avascular tissue made up largely of cartilage-specific cells, the chondrocytes, proteoglycans and collagen proteins, which are structural proteins that provide structural strength to connective tissue, such as skin, bone and cartilage. Collagen II, together with the protein collagen IX, forms a "biological alloy", which is molded into a fibril-like structure and is arranged in a precise network, providing cartilage with great mechanical strength. The chondrocytes in normal articular cartilage occupy approximately 5% of the tissue volume, while the extra-cellular matrix makes up the remaining 95% of the tissue. The chondrocytes secrete the components of the matrix, which in turn supplies the chondrocytes with an environment suitable for their survival under mechanical stress. [0004] Breakdown of articular cartilage, which is part of joints and which cushions the ends of the bones, causes the bones to rub against each other leading to pain and loss of movement. Cartilage degradation may also be the result of an imbalance in cartilage synthesizing (anabolic) and cartilage degrading (catabolic) processes. Unlike most tissues, cartilage does not self-repair following injury. The inability of cartilage to self-repair after injury, disease, or surgery is a major limiting factor in rehabilitation of degrading joint surfaces and injury to meniscal cartilage. [0005] There are many diseases involving the degeneration of cartilage. Rheumatoid arthritis and osteoarthritis are among the most prominent. Osteoarthritis (also referred to as OA, or as wear-and-tear arthritis) is the most common form of arthritis and is characterized by loss of articular cartilage, often associated with hypertrophy of the bone. The disease mainly affects hands and weight-bearing joints such as knees, hips and spines. This process thins the cartilage through a phenomenon called apoptosis, or programmed cell death. When the surface area has disappeared due to the thinning, there is a grade I osteoarthritis; when the tangential surface area has disappeared, there is a grade two osteoarthritis. There are other levels of degeneration and destruction, which affect the deep and the calcified layers that border with the subchondral bone. [0006] The clinical manifestations of the development of the osteoarthritis condition are: increased volume of the joint, pain, crepitation and functional disability that, gradually and steadily, first hinders the performance of lengthy walks and forced flexion and extension movements, depending on the affected joint, and then pain and limitation of minimum efforts emerge as well as pain at rest which interrupts sleeping. If the condition persists without correction and/or therapy, the joint is destroyed, leading the patient to major replacement surgery with total prosthesis, or to disability. [0007] Therapeutic methods for the correction of the articular cartilage lesions that appear during the osteoarthritic disease have been developed, but so far none of them have been able to achieve the regeneration of articular cartilage in situ and in vivo. REPORTED DEVELOPMENTS [0008] Osteoarthritis is difficult to treat. At present, no cure is available and treatment focuses on relieving pain and preventing the affected joint from becoming deformed. Common treatments include the use of non-steroidal anti-inflammatory drugs (NSAID's), which are often used to relieve pain, while specific COX-2 inhibitors are used to relieve severe pain. Medicines such as chondroitin and glucosamine are thought to improve the cartilage itself. These treatments may be relatively successful, but not a substantive amount of research data is available. [0009] In severe cases, joint replacement may be necessary. This is especially true for hips and knees. If a joint is extremely painful and cannot be replaced, it may be fused. This procedure stops the pain, but results in the permanent loss of joint function, making walking and bending difficult. [0010] The treatment that has 74% to 90% effectiveness and produces excellent results is the transplantation of cultured autologous chondrocytes, by taking chondral cellular material from the patient, sending it to a laboratory where it is seeded in a proper medium for its proliferation, and, once enough volume is achieved after a variable period that may last from weeks to months, transporting it in a special container and implanting it in the damaged tissues to cover the tissue's defects. [0011] Another treatment includes the intraarticular instillation of Hylan G-F 20 (Synvisc, Hyalgan, Artz etc.), a substance that improves temporarily the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain. The residual effects of this substance act on the synovial receptors causing a pain reduction that lasts several weeks and even months. However, this isolated effect is counterproductive for the course of the disease and for the viability of the cartilage because, as it masks the symptoms, the joint is used with more intensity and its destruction is accelerated as the original problem is not corrected and the damaged articular cartilage is not restored. [0012] Other reported methods include application of tendinous, periosteal, fascial, muscular or perichondral grafts; implantation of fibrin or cultured chondrocytes; implantation of synthetic matrices, such as collagen, carbon fiber; administration of electromagnetic fields. All of these have reported minimal and incomplete results with formation of repair, but not regenerative tissue, resulting in a poor quality tissue that can neither support the weighted load nor allow the restoration of an articular function with normal movement. [0013] Stimulation of the anabolic processes, blocking catabolic processes, or a combination of these two, may result in stabilization of the cartilage, and perhaps even reversion of the damage, and therefore prevent further progression of the disease. Various triggers may stimulate anabolic stimulation of chondrocytes. Insulin-like growth factor-I (IGF-I) is the predominant anabolic growth factor in synovial fluid and stimulates the synthesis of both proteoglycans and collagen. It has also been shown that members of the bone morphogenetic protein (BMP) family, notably BMP2, BMP4, BMP6, and BMP7, and members of the human transforming growth factor-b (TGF-b) family can induce chondrocyte anabolic stimulation (Chubinskaya and Kuettner, 2003). A compound has recently been identified that induces anabolic stimulation of chondrocytes (U.S. Pat. No. 6,500,854; EP 1.391211). However, most of these compounds show severe side effects and, consequently, there is a strong need for compounds that stimulate chondrocyte differentiation without severe side effects. [0014] The present invention relates to the relationship between the function of selected proteins identified by the present inventors (hereinafter referred to as "TARGETS") and anabolic stimulation of chondrocytes. SUMMARY OF THE INVENTION [0015] The present invention relates to a method for identifying compounds that induce cartilage-synthesizing processes, which lead to anabolic stimulation of chondrocytes, comprising contacting the compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594, or a functional fragment or derivative thereof, under conditions that allow said polypeptide to bind to the compound, and measuring a compound-polypeptide property related to the anabolic stimulation of chondrocytes. [0016] The present invention also relates to expression inhibitory agents, pharmaceutical compositions comprising the same, methods for the in vitro production of cartilage tissue, and host cells expressing said agents. [0017] Aspects of the present method include the in vitro assay of compounds using polypeptide of a TARGET, and cellular assays wherein TARGET inhibition is followed by observing indicators of efficacy, including collagen type II, alpha-1 (col2.alpha.1) and aggrecan levels. [0018] Another aspect of the invention is a method of treatment or prevention of a condition involving de-differentiation of chondrocytes and/or loss of cartilage thickness, in a subject suffering or susceptible thereto, by administering a pharmaceutical composition comprising an effective cartilage formation-enhancing amount of a TARGET inhibitor. [0019] A further aspect of the present invention is a pharmaceutical composition for use in said method wherein said inhibitor comprises a polynucleotide selected from the group of an antisense polynucleotide, a ribozyme, and a small interfering RNA (siRNA), wherein said inhibitor comprises a nucleic acid sequence complementary to, or engineered from, a naturally occurring polynucleotide sequence encoding a polypeptide, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594, or a fragment thereof. [0020] Another further aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective cartilage formation-enhancing amount of a TARGET inhibitor or its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof in admixture with a pharmaceutically acceptable carrier. The present polynucleotides and TARGET inhibitor compounds are also useful for the manufacturing of a medicament for the treatment of conditions involving de-differentiation of chondrocytes and/or cartilage thickness loss. Continue reading... Full patent description for Method and means for treatment of osteoarthritis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method and means for treatment of osteoarthritis patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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