Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-12
2004-02-24
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06696454
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the involvement of spermidine synthase with the development of osteoarthritis and in cartilage rehabilitation. More particularly, the invention relates to methods of treatment, compositions and the use of spermidine synthase inhibitors in the treatment of osteoarthritis and cartilage damage associated therewith.
BACKGROUND OF THE INVENTION
Osteoarthritis (OA) is a common, debilitating, costly, and currently incurable disease. Novel approaches to therapy are clearly required. The disease is characterized by abnormal functioning of chondrocytes, their terminal differentiation and initiation of osteogenesis within articular cartilage tissue, and breakdown of normal cartilage matrix. Genes whose products are involved in chondrogenesis and osteogenesis starting from the common progenitor cells, genes determining the terminal differentiation of chondrocytes and genes whose products trigger breakdown of the cartilaginous matrix are obvious candidates for therapeutic intervention.
Epidemiology of OA
OA, also erroneously called degenerative joint disease, represents failure of a diarthrodial (movable, synovial-lined) joint. In idiopathic (primary) OA, the most common form of the disease, no predisposing factor is apparent.
Secondary OA is pathologically indistinguishable from idiopathic OA but is attributable to an underlying cause. OA is the most common of all human joint disorders and is the most prevalent arthritic condition in the United States and around the world. Estimates of OA prevalence based on clinical evaluation in various studies show that more than 90% of the population over the age of 70 has OA. The invention is aimed at novel avenues of therapy and prevention of the disease.
Pathogenesis of OA
OA is a heterogeneous group of conditions that lead to joint symptoms and signs associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins. OA may be either idiopathic (i.e., primary) or secondary to other medical conditions (inflammatory, biochemical, endocrine-related, metabolic, and anatomic or developmental abnormalities). Age is the most powerful risk factor for OA but major trauma and repetitive joint use are also important risk factors for OA. The pattern of joint involvement in OA is also influenced by prior vocational or avocational overload.
The disease has two general stages: (1) compensated and (2) decompensated. Currently, most investigators feel that the primary changes occur in cartilage extracellular matrix due to exogenous reasons (i.e., load, injury etc.). Then, a defect in the collagen network of the cartilage is apparent, and lysosomal enzymes and secreted proteases (MMPs, plasmin, cathepsins) probably account for the observed initial alterations in cartilage matrix. Their synthesis and secretion are stimulated by IL-1 or by other factors (e.g., mechanical stimuli). In the initial stage of disease, compensatory cellular response is activated. Secreted by chondrocytes, protease inhibitors like TIMP and PAI-1 work to stabilize the system by opposing the protease activity. Growth factors such as IGF-1 and TGF-&bgr; are implicated in repair processes that may heal the lesion or, at least, stabilize the process by activating proliferation of cells of chondrogenic lineage. Finally, this leads to the accumulation of hypertrophic chondrocytes. The latter cells have marked biosynthetic activity that is expressed in increasing the proteoglycan (PG) concentration, associated with thickening of the cartilage (“compensated” OA). The compensatory mechanisms may maintain the joint in a reasonably functional state for years. However, the repair tissue does not hold up and the rate of PG synthesis falls off with full-thickness loss of cartilage. This marks the decompensated stage of OA. Following the destruction of the articular cartilage, there is migration of progenitor cells to the sites of tissue damage. These cells proliferate and differentiate into four cell types: osteoblasts, chondroblasts, chondroclasts and fibroblasts, which combine to form bony structures called osteophytes which protrude into the joint space, thus inhibiting its movement. Finally, gradual replacement of cartilage with bone occurs.
The reason for this phenomenon is unknown. One possibility is that in OA, the normal inhibitory growth control of articular chondrocytes or synovial membrane fibroblasts is altered. This enables accumulation of two types of cells that cannot be found in normal articular cartilage: (1) immature mesenchymal and bone marrow cells with modified properties, and (2) hypertrophic articular chondrocytes. Previous results have clearly shown that hypertrophic chondrocytes may trigger osteogenesis by secretion of angiogenic and osteogenic factors. (Homer, A., Bishop, N. J., Bord S., Beeton, C., Kelsall, A. W., Coleman, N. and Compston, J. E. (1999). Immunolocalisation of vascular endothelial growth factor (VEGF) in human neonatal growth plate cartilage. J. Anat. 194: 519-524).
In OA, therapeutic interference may target three main processes:
inhibition of initial cartilage damage—one of the accepted therapeutic strategies, combining recommendations to reduce the physical pressure on the joint and treatment with inhibitors of metalloproteinases;
inhibition or attenuation of total cartilage destruction at later stages—implies the therapeutic activation of processes connected to cartilage rehabilitation, namely, the promotion of proper differentiation of mesenchymal progenitors into mature chondrocytes capable of producing fully functional articular cartilage tissue;
inhibition or attenuation of osteophyte formation at the end stage of the disease—implies the therapeutic inhibition of ectopic osteogenesis at the site of articular cartilage.
Therefore, the inventors set out to identify target genes that code for specific factors that stimulate or inhibit the differentiation of progenitor cells to chondrocytes and/or stimulate or inhibit the differentiation of progenitor cells to osteoblasts.
Changes in gene expression caused by IL-1, FGF-2 and mechanical stress, which are known osteogenic factors, may be connected to OA development and, therefore, should be opposed by therapeutic intervention. Surprisingly, it has been found by the present inventors that one of the genes that were upregulated by FGF-2 is the spermidine synthase gene. This implied that the spermidine synthase gene might be involved in the OA pathway.
Spermidine Synthase
Spermidine is one of three bioactive polyamines, the other two being putrescine and spermine. Polyamines constitute a group of cell components that are important in the regulation of cell proliferation and cell differentiation. Although their exact functions have not yet been clarified, it is assumed that polyamines play an important role in a number of cellular processes such as replication, transcription, and translation.
The polyamine biosynthetic pathway consists of two highly regulated enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, and two constitutively expressed enzymes, spermidine synthase and spermine synthase. Spermidine synthase is a 74 kDa protein that catalyses the 3-aminopropylation of putrescine (1,4-diaminobutane) to produce spermidine. The biosynthesis of spermidine involves decarboxylation of S-adenosylmethionine (SAM) to S-adenosyl-3-methylthiopropanamine (decarboxylated SAM) by SAM decarboxylase, and decarboxylation of ornithine to putrescine by ornithine decarboxylase. Decarboxylated SAM then reacts with spermidine synthase to generate an aminopropylated form of the enzyme, which then transfers the aminopropyl group to putrescine to produce spermidine and 5′-methylthioadenosine (MTA). The active enzyme is a dimer of two identical subunits, requires no cofactors, and uses dcAdoMet as an aminopropyl donor and putrescine as the acceptor.
Putrescine, spermidine and spermine have been found in many living tissues, including cartilage. Their formation, catalyzed by ODC, has been observed
Bar Dganit
Feinstein Elena
Segev Orit
Cooper & Dunham LLP
Criares Theodore J.
Quark Biotech, Inc.
White John P.
LandOfFree
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