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WO1994028889A1 - Composes synthetiques et naturels purifies pour le traitement de l'osteo-arthrite - Google Patents

Composes synthetiques et naturels purifies pour le traitement de l'osteo-arthrite Download PDF

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Publication number
WO1994028889A1
WO1994028889A1 PCT/US1994/006490 US9406490W WO9428889A1 WO 1994028889 A1 WO1994028889 A1 WO 1994028889A1 US 9406490 W US9406490 W US 9406490W WO 9428889 A1 WO9428889 A1 WO 9428889A1
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Prior art keywords
glycosaminoglycan
purified
species
proteoglycan
growth factor
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PCT/US1994/006490
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English (en)
Inventor
Peter T. Lansbury, Jr.
Peter V. Hauschka
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Neogenix, Inc.
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Publication date
Application filed by Neogenix, Inc. filed Critical Neogenix, Inc.
Priority to AU72058/94A priority Critical patent/AU7205894A/en
Publication of WO1994028889A1 publication Critical patent/WO1994028889A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types

Definitions

  • the present invention relates to individual, well-defined compounds and the uses of these compounds, alone and in conjunction with bioactive molecules such as growth factors or metalloproteinase inhibitors, for the repair of cartilage damage as, for example, is found in osteoarthritis.
  • bioactive molecules such as growth factors or metalloproteinase inhibitors
  • Such well- defined compounds may include, but are not limited to, purified components of the extracellular matrix (ECM) , derivatives of these ECM components, and glycosaminoglycan (GAG) mimics.
  • ECM extracellular matrix
  • GAG glycosaminoglycan
  • the present invention provides methods for the selection of those compounds which have an increased capacity for cartilage repair.
  • CARTILAGE Cartilage is a hard connective tissue whose unique material properties of durability, stiffness, resiliency, and viscoelasticity make possible the normal function of the musculoskeletal, auditory and respiratory systems.
  • essential structural components are comprised of cartilage, including synovial joints, which consist of articular hyaline cartilage, and intervertebral disks, and parts of the insertions of tendons and ligaments into bone, all of which consist of fibrous cartilage.
  • Cartilage lacks nerves, and lymph and blood vessels, but cells within the tissue, however, are metabolically active, responding to hormonal changes, nutrient availability, oxygen tension, and mechanical loads.
  • Cartilaginous tissue consists of three components: chondrocytes, extracellular water, and an abundant ECM.
  • the tissue is formed as groups of chondrocytes gather and secrete a cartilagineous ECM which surrounds the cells. In most mature cartilage, chondrocytes contribute only about 5% of the total tissue volume, while the ECM makes up the remaining 95%.
  • Tissue fluid comprises the largest component of cartilage; depending on the type and age of the cartilage, extracellular water can contribute up to 80% of the tissue's wet weight.
  • extracellular water can contribute up to 80% of the tissue's wet weight.
  • TGF-3 the growth factor TGF-3, which stimulates the proliferation of many cell-types, including chondrocytes (Sporn, M.B. et al..
  • the major component of the cartilaginous ECM are collagen fibers, with type II collagen being the most abundant subtype present in hyaline cartilage, and type I collagen being most abundant in fibrous cartilage. (Miller, E.J., 1976, Mol. Cell. Biochem. 11:165-191).
  • proteoglycans are another major component of hyaline cartilage ECM. (Heingard, D. , 1977, J. Biol. Chem. Z52:1980-1989) .
  • Proteoglycans are molecules consisting of protein bound by polysaccharide glycosaminoglycan (GAG) chains.
  • GAG chains are comprised of repeating disaccharide units containing a derivative of either glucosamine or galactosamine.
  • each disaccharide unit contains at least one negatively charged carboxylate or sulfate group, such that GAGs form long strings of negative charges.
  • Cartilage GAGs include hyaluronic acid, chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, and keratan sulfate.
  • Cartilaginous proteoglycans exists in nonaggregating and aggregating monomer forms.
  • Aggregating monomers make up the bulk (85-98%) of the proteoglycan population, and consist of protein cores to which oligosaccharides and the GAGs chondroitin sulfate and keratan sulfate are bound.
  • the aggregating proteoglycans can exist as monomers or as groups of multiple monomers plus hyaluronic acid and small proteins known as link proteins.
  • the negative charges along GAG chains allow proteoglycans to bind cations and a large volume of water. Because adjacent, negatively charged GAG chains repel each other, proteoglycan molecules tend to remain in an extended form, and the water is drawn inside, creating swelling pressure within the matrix.
  • the collagen network limits proteoglycan swelling, but loss or damage to the network allows cartilage to swell, resulting in an increased water concentration and a decreased proteoglycan concentration, ultimately leading to cartilaginous tissue damage.
  • OA Osteoarthritis
  • OA is characterized by joint pain, tenderness, limitation of movement, crepitus, and inexorably progressive disability.
  • Pathologic changes in the once smooth cartilage surfaces include cartilage fissuring, pitting, and erosion. Erosions, initially focal, become confluent, leading to large areas of denuded surface and eventually to loss of cartilage down to the bone. The bone tissue directly under the cartilage develops cysts, becomes thickened, and the entire end of the bone exhibits hypertrophy, resulting in the loss of congruity of the cartilage surfaces. This loss leads to increased joint instability, which, in turn, leads to further stress on joint tissues, causing inflammation and seepage of joint fluid into the surrounding tissues.
  • OA cartilage ECM contains a reduced level of proteoglycans, which play an important role in the structural integrity of cartilage (Mankin, et al. f 1971, J. Bone Joint Surg. 53A:523-537; Erlich, 1985, J. Orthop. Res. 3_:170-184). Also, a smaller than normal proportion of the total proteoglycan population is present in aggregates, and GAG chains are, on average, shorter than normal (Maroudas, A. et al.. 1973, Ann. Rheum. Dis. 3_2:l-9; Mankin, H.J., 1974, N.
  • Cartilage also contains a molecule termed tissue inhibitor of metalloproteinases (TIMP) (Dean, D.D. and Woessner, J.F., 1984, Biochem. J. 218:277-280: Dean, D.D. et al.. 1987, J. Rheumatol. .14.: (Suppl.) 43-44), which inhibits metalloproteinases and collagenase. While in OA, the concentration of TIMP is either modestly increased or unchanged, metalloproteinase levels are increased 3-5 fold (Azzo, W. et al.. 1986, J. Biol. Chem. 261:5434-5441; Dean, D.D. et al. f 1987, J.
  • TIMP tissue inhibitor of metalloproteinases
  • Nondrug treatment alternatives range from patient education concerning joint protection, to devices, such as walkers or canes, employed to correct abnormalities of the feet, to, finally, total surgical replacement of the OA joint.
  • Drugs used for the treatment of OA symptoms include analgesics (i.e.. aspirin, acetaminophen, or ibuprofen) or non-steroidal anti-inflammatory drugs (NSAIDS) , which are employed to simply relieve pain and inflammation (Husby, G. et al.. 1986, Clin. Rheumatol. 5_:84-91; Davis, P., 1987, J. Rheumatol. 14.:94-97).
  • NSAIDS are one of the major groups of drugs in terms of sales and use for the management of OA among the general population (Bjelle, A. et al.. 1984, J. Rheumatol. 11:493-499)
  • their side effects have become a problem (Wilholm, B.E. et al.. 1985, in Side Effects of Anti- Inflammatory Drugs, Rainsford, K.D. and Velo, G.P. eds., MTD Press Ltd., Lancaster, pp. 55-72), particularly in the elderly (Buchanan, W.W. and Kean, W.F., 1987, J. Rheumatol. 11:98-100).
  • NSAIDS cause gastrointestinal hemorrhage, ulceration, or perforation, while some are associated with bone marrow depression, several cause fluid retention, and some may contribute to renal failure. These effects are particularly important because such treatments are often long-term and the reactions may be serious, even potentially fatal, especially in elderly patients. Also, the long-term application of NSAIDS or analgesics may exacerbate the progress of OA, both because of overuse of joints that are pain-free due to the drugs' properties, and, in the case of NSAIDS, by the drugs' effects on biochemical mechanisms such as cartilage and chondrocyte metabolism.
  • Therapeutic agents which have disease-modifying potential, rather than functioning solely to alleviate symptoms, are of great interest for the treatment of OA.
  • the treatment aim would be to stimulate cartilage repair and to, concurrently, inhibit cartilage breakdown by suppressing the degradative effect of enzymes on cartilage while sustaining chondrocyte metabolic activity.
  • Such agents termed “chondroprotective,” are specifically directed toward the prevention, retardation, or reversal of the OA process (Burkhardt, D. et al.. 1987, Arth. Rheum. .17:3-34).
  • Rumalon® Robotic, Ltd., Basel, Switzerland; Rejholec, V., 1987, Semin. Arth. Rheum.
  • Rumalon® is a mixture of ECM components in a high molecular weight (10 5 -2xl0 6 D) GAG-peptide associated complex which is derived from bovine cartilage and bone marrow. Studies indicate that this complex is non-covalent and that much of its biological activity is due to its peptide components (Burkhardt, D. and Ghosh, P., 1987, Semin. Arth. Rheum. r7:3-34).
  • Arteparon® consists of a mixture of GAG polysulfuric acid esters (molecular weight, 10 4 -2xl0 4 D) of oversulfated GAG chains containing galactosamine and hexuronic acid (Golding, J. and Ghosh, P., 1983, Curr. Therapy Res. 34:67-80) . which is derived from bovine lung and tracheal tissue.
  • the present invention relates to individual, well-defined compounds and to the uses of these compounds, alone and in conjunction with bioactive molecules, for the repair of damaged cartilage tissue of the type, for example, that is found in osteoarthritis (OA) .
  • Such well-defined compounds may include, but are not limited to, purified components of the ECM, derivatives of these components, and GAG mimics.
  • the bioactive molecules that can be used in conjunction with these compounds may include, for example, growth factors or metalloproteinase inhibitors.
  • the invention describes methods for the purification and/or modification of the ECM components, and the synthesis of the GAG mimics. Further, the invention provides methods for the selection of those compounds which have an increased capacity for cartilage repair.
  • ECM components of the present invention are well-defined molecules which, therefore, provide, for the first time, a means by which to optimize both the safety and cartilage healing properties of therapeutic formulations.
  • Such purified ECM components may include, but are not limited to, specific GAGs, such as a single species of chondroitin sulfate. GAG mimics have never been utilized for the alleviation of OA.
  • Such compounds may include, but are not limited to, sulfated polysaccharides, sulfated aromatic dyes, or sulfated polysaccharide-like oligomers. 4. DETAILED DESCRIPTION OF THE INVENTION
  • This invention involves single, well-defined compounds and their uses, alone and in combination with other bioactive molecules, for the repair of damaged cartilage tissue as, for example, is found in OA.
  • These well-defined compounds may include, but are not limited to, purified ECM components, derivatives of these components, and GAG mimics. Additionally, the invention provides means for the selection of compounds which have an increased capacity for cartilage repair.
  • Described below are methods for the purification of specific ECM components from various sources, techniques for the modification of such components and procedures for the synthesis of GAG mimics.
  • methods are presented describing the administration of formulations containing these well- defined compounds for the repair of damaged cartilage and the treatment of OA. Further, screening techniques are described that allow for the selection of candidate cartilage repair compounds.
  • the individual purified ECM components of the invention may include, but are not limited to, single, well-defined species of glycosaminoglycan (GAG) polysaccharides or proteoglycans.
  • GAG glycosaminoglycan
  • a single well-defined species of GAG refers, here, to a species of a narrow molecular weight range (i.e.. +/- 1000 daltons) , polysaccharide composition, and sulfation pattern.
  • a single well-defined species of proteoglycan refers to a species of a single molecular weight range (i.e.. +/- 1000 daltons) , core protein identity, and GAG modification pattern.
  • the GAGs may consist of repeating linear polymers of specific disaccharides.
  • one sugar of such disaccharide units is either a hexuronic acid (HexA; i.e. D-glucuronic acid (GlcA) or L-iduronic acid (IdoA) ) or a galactose monosaccharide, and the other sugar of the disaccharide unit is a hexosamine (i.e.. D-glucosamine (GlcN) or D-Galactosamine (GalN) .
  • HexA hexuronic acid
  • GlcA D-glucuronic acid
  • IdoA L-iduronic acid
  • GalN D-Galactosamine
  • the individual purified GAG chains of the invention may include, but are not limited to, a basic structure composed of (HexA-GalN) n , (Hex A- GlcN) n , (Gal-GlcN) n , (GlcNAc-GlcNAc) or (Gal-GalN) n disaccharide units, where n is the number of disaccharide units within the GAG chain.
  • n is the number of disaccharide units within the GAG chain.
  • One or both of the sugars within each disaccharide unit is sulfated at one or two positions.
  • each individual chain may include, for example, differences in sulfate substitution along the chain and epimerization of specific monosaccharides within the chain (GlcA to IdoA, for example) .
  • the purified GAG chains of the invention may include, but are not limited to, individual species of chondroitin-4-sulfate, chondroitin-6- sulfate, hyaluronic acid, heparin, heparin sulfate, keratan sulfate, dermatan sulfate, or poly-N-acetyl- glucosamine, poly-N-glucosamine, and their derivatives.
  • the proteoglycans of the invention which consist of core proteins to which one or more GAG polysaccharides is covalently attached, likewise consist of a well-defined, purified species. Each of these proteoglycans is of a narrow molecular weight range (i.e.. +/- 1000 daltons) , core protein identity, and GAG modification pattern.
  • the homogeneous, individual ECM components of the invention may be purified from heterogenous starting sources.
  • the starting sources may include, but are not limited to, heterogenous populations of groups of GAG molecules which may consist, for example, of widely varying molecular weight populations of heparin sulfate, chondroitin-4-sulfate, chondroitin-6-sulfate, chitin, or chitosan.
  • more complex mixtures including, but not limited to, Arteparon® or Rumalon® may be utilized as starting sources for ECM component purification.
  • a general scheme by which purified GAG and/or proteoglycan ECM components may be obtained from a heterogenous mixture of molecules involves a stepwise reduction in heterogeneity until a purified species of molecules is obtained.
  • the complexity of GAG species may be reduced by treatment of the mixture with agents that attack specific groups along GAG chains.
  • a further reduction of GAG complexity may be obtained by separating the components of the mixture according to molecular weight.
  • individual species may be obtained by separating the components of any given molecular weight class by such techniques of HPLC.
  • the agents which attack specific groups along GAG chains are the Eliminase class of enzymes which cleave at uronic acid residues and which include, for example, heparinase (EC 4.2.2.7), chondroitinase ABC (EC 4.2.2.4), chondroitinase AC (EC 4.2.2.5), and chitinase (EC 3.2.1.14).
  • a mixture may be treated with nitrous acid (HONO) , which attacks N-acetyl-D-glucosamine monosaccharide units, resulting in chain cleavage.
  • HONO nitrous acid
  • the average sizes and number of GAG species generated after treatment may be modulated by varying the concentration of agent used and time of agent exposure.
  • the lower limit for a GAG molecule of the invention will be one consisting of 2- 3 monosaccharide units. While there is no strict upper limit for the number of constituent monosaccharide units, the preferred upper limit will be 10-15 monosaccharide units per GAG molecule, and will most preferably consist of 6-8 monosaccharide units per molecule.
  • the heterogeneity of the mixture may be further reduced by separating elements of the mixture according to molecular weight. Separation may be accomplished by gel filtration and/or ion exchange chromatography. Each molecular weight class thus separated consists of a group of oligomers (e.g. , of 2, 4, 6, 8, etc. monosaccharides depending on the molecular weight class) . It is important to note that, because each of the agents described above attacks different groups along the GAG chain, the composition of molecules in a single molecular weight class will differ according to which treatment was administered prior to molecular weight separation.
  • HPLC high performance liquid chromatography
  • the purified ECM components of the invention described in this section may be modified using a variety of techniques which are well known to those of ordinary skill in the art. Such techniques modify GAGs at specific groups along a GAG chain, and may be applied before and/or after separation according to molecular weight and/or HPLC purification.
  • GAGs may be further sulfated by the addition of sulfate groups to amino (-NH 2 ) and/or hydroxyl groups (-0H) along the polysaccharide chain. Sulfation may be achieved via addition sulfur trioxide in pyridine.
  • GAG chain hydroxyl groups may be acylated and/or carboxyl groups (-C0 2 H) may be esterified (-C0 2 S, where "S" may be an aryl, alkyl, alkenyl, or alkynyl moiety) .
  • Acylation of hydroxyl groups made be achieved by treatment with acyl chlorides in pyridine.
  • Esterification of carboxyl groups may be performed by activation with dicyclohexyl carbodii ide in an alcohol. The identity of the alcohol is dependent upon the identity of the desired resulting ester(s) .
  • acylated groups may be deacylated, or amino groups may be aminated (-NHT, where "T” may be an aryl, alkyl, alkenyl, or alkynyl moiety.
  • Deacylation may accomplished with the addition of lithium in water.
  • the amidation of amine groups may be accomplished by treatment with acyl chlorides in pyridine.
  • nucleophilic modification of the Eliminase product(s) may be performed by Michael addition of thiols (i.e.. thiol and lithium hydroxide) .
  • the well-defined compounds of the invention may also include GAG mimics.
  • GAGs play an essential role in conferring onto cartilaginous tissue its unique material properties such as durability, stiffness, resiliency, and viscoelasticity.
  • GAG mimics therefore, refer here to molecules possessing the ability to substitute or partially substitute, for the presence of GAG molecules in conferring onto cartilage at least some of its essential properties, which include, but are not limited to, those described above.
  • sulfated homopolymers or heteropolymers ranging from about 2 to about 15 monomeric units per molecule, with molecules ranging from about 6 to about 10 monomeric units being preferred.
  • Each of the monomeric units should be sulfated or sulfatable, i.e. , should contain 1) at least one amino (-NH 2 ) or hydroxyl (-0H) group to which a sulfate group may be attached, or 2) at least one -S0 4 " or -NS0 3 ' group.
  • the ratio of sulfates to monosaccharide units should, on average, be at least 0.5 (i.e.
  • each monomeric unit may contain a carboxyl (-COOH) , carboxylate (-COO") or carboxoate (-COOU, where "U” may be an alkyl, alkenyl, alkynyl, or aryl moiety) group.
  • a GAG mimic monomeric unit of the type provided for herein can, therefore, be represented as in (I) , solely for the purposes of illustration and not by way of limitation:
  • R can include, but is not limited to, any simple monomeric unit or polymerizable unit including, but not limited to a hexuronic acid (Hex A; i.e. D- glucuronic acid (GlcA) or L-iduronic acid (IdoA) a galactose monosaccharide, hexosamine (i.e..
  • "a” can include, but is not limited to -OH, -S0 4 ", or -COV (where “V” may be an aryl, alkyl, alkenyl, or alkynyl moiety;
  • "b” can include, but is not limited to, -NH 2 , - NSO j J or -NHT (where “T” may be an alkyl, alkenyl, alkynyl, or aryl moiety);
  • “c” can include, but is not limited to -COOH, -COO', or -COOU (where “U” may be an alkyl, alkenyl, alkynyl, or aryl moiety);
  • A", "B” and “Z” are integers ranging from 0 to 30, and the sum of A and B is greater than or equal to 1.
  • a GAG mimic of the type provided herein can be represented as in (II) , solely for the purposes of illustration and not by way of limitation:
  • R, a, b, c, A, B, and Z are as described in (I) , and , which represents the total number of monomeric units within a GAG mimic, is an integer ranging from about 2 to about 15, with 6 to 10 being preferred.
  • Each monomeric unit(s) is(are) covalently linked to its adjacent monomeric unit(s) .
  • the ratio of the sum of all sulfations per GAG mimic, (i.e. , the sum of all A wherein a A equals -S0 4 " plus the sum of all B wherein b or b B equals -NS0 3 ") to w must be greater than or equal to 0.5.
  • each monomeric unit, within the GAG mimic may differ from all other monomeric units within the mimic. That is, the monomer constituents (R, a A , b B , c z ) need not be identical with respect to each monomeric unit.
  • GAG mimics sulfated homopolymers or heteropolymers of aromatic compounds, which include, but are not limited to aromatic dyes such as Congo Red and Suramin.
  • aromatic compounds within this group of potential GAG mimics may be used, or, alternatively, unique aromatic polymers may be synthesized. Synthesis techniques by which such polymers may be made include standard solid phase or solution condensation or polymerization chemistry.
  • sulfated polysaccharide-like molecules such as Suramin or Suramin analogs.
  • Known compounds within this group of potential GAG mimics may be used, or unique polysaccharide-like molecules may be obtained as, for example, degradation products of larger polysaccharides.
  • Such degradation procedures may include standard enzymatic (for example, Eliminase cleavage) and/or chemical (for example, nitrous acid treatment) procedures.
  • GAG mimics may be further sulfated by the addition of sulfate groups to amino (-NH 2 ) and/or hydroxyl groups (-0H) along the GAG mimic chain.
  • GAG mimic chain hydroxyl groups may be acylated and/or carboxyl groups (-C0 2 H) may be esterified (-C0 2 S, where "S" may be an alkyl, alkenyl, alkynyl, or aryl moiety) .
  • acylated groups may be deacylated, or amino groups may be aminated (-NHT, where "T” may be an alkyl, alkenyl, alkynyl, or aryl moiety) .
  • nucleophilic modification of the Eliminase product(s) may be performed by Michael addition of thiols.
  • the purified compounds of the invention may be used alone or in conjunction with bioactive molecules for the repair of damaged cartilage such as is seen in OA.
  • bioactive molecules may include, but are not limited to growth factors and/or metalloproteinase inhibitors.
  • Growth factors that may be used in conjunction with the purified compounds of the invention include, but are not limited to cartilage-derived growth factors, members of the TGF-3 growth factor superfamily, connective tissue activating peptides, platelet-derived growth factor, fibroblast growth factor, and insulin and insulin-like growth factors I and II.
  • Metalloproteinase inhibitors that may be used in conjunction with the purified compounds of the invention include, but are not limited to tissue inhibitors of metalloproteinases (TIMP1 and TIMP2) and plasminogen activator inhibitor (PAI-1) .
  • SCREENING METHODS Molecules which include, but are not limited to those of the type described in Sections 4.1, and 4.2 above, may be screened, using a variety of techniques, for their ability to repair damaged cartilage.
  • candidate cartilage repair molecules may be initially selected for their ability to bind bioactive molecules known to influence cartilage metabolism.
  • candidate cartilage repair molecules may be tested for their effects on chondrocyte cell cultures and/or OA animal models. These molecules may be tested alone, and in conjunction with bioactive molecules which include, but are not limited to the types described above, in Section 4.3.
  • Potential candidate cartilage repair molecules may be initially selected via their ability to bind bioactive molecules known to influence cartilage metabolism.
  • the bioactive molecules that may be used in such a screening technique include, but are not limited to, those described, above, in Section 4.3. Briefly, such a screening technique may consist, first, of incubation of test compounds, individually or in a mixture, in the presence of bioactive molecules known to influence cartilage metabolism.
  • bioactive molecules of this screening technique may be attached to a solid matrix, including, but not limited to agarose or plastic beads, microtiter wells, or petri dishes. After incubation, those compounds with no appreciable affinity for the bioactive molecule do not become attached to the solid matrix and may, therefore, be removed by rinsing of the matrix. Following removal of unbound compounds, the bound compounds may be eluted away from the bioactive molecules and recovered. Such bound compounds may be eluted using standard techniques which include, but are not limited to an alteration of ionic strength, alteration of pH, and/or by the addition of chaotropic eluants.
  • the compounds and bioactive molecules may both exist free in solution during the incubation process.
  • the bioactive molecules may be removed from solution using, for example, standard immunoprecipitation techniques. Because any compound bound to the bioactive molecule would also be removed from solution, those compounds with an appreciable affinity for the bioactive molecules in use may be selected.
  • Candidate cartilage repair molecules may also be screened using human chondrocyte cell culture systems.
  • Human chondrocytes either normal or OA, may be isolated directly from sterile cartilage specimens which have been obtained from the hip or knee joint at the time of surgery or autopsy.
  • the chondrocytes may be isolated from the specimens using techniques which are well known to those of ordinary skill in the art, and which may include treatment of the specimens by successive digestions with hyaluronidase, trypsin, and collagenase as described in Schwartz, E.R. (Cartilage Cells and Organ Culture, in Skeletal Research: An Experimental Approach, Simmons, D.J.
  • chondrocytes may be suspended in Ham's F12 medium (Ham, R.G., 1965, Proc. Natl. Acad. Sci. USA 53:288; Ham, R.G. and Murray, L.W. , 1967, S. Cell Physiol. 7_0:275; Pechl, D.M.
  • cell culture media is supplemented with varying concentrations of test compounds, i.e. , candidate cartilage repair molecules for varying lengths of time.
  • the cell culture media may also be supplemented with varying concentrations of bioactive molecules in conjunction with the candidate cartilage repair molecules.
  • test compounds i.e. , candidate cartilage repair molecules for varying lengths of time.
  • the cell culture media may also be supplemented with varying concentrations of bioactive molecules in conjunction with the candidate cartilage repair molecules.
  • Both normal and OA chondrocyte cell cultures will be treated with candidate cartilage repair molecules.
  • qualitative and quantitative effects on the cultures including but not limited to growth rates, ECM composition, and concentrations of various metalloproteinases, growth factors, growth factor receptors, inhibitors and activators of cell division and/or differentiation and other cellular factors can be measured.
  • These measurements are also made on untreated OA cell cultures as well as treated and untreated normal cell cultures. Comparisons are made between the measurements obtained each of these types of cell samples, and are used to score
  • Chondrocyte growth rates may be measured using a DNA synthesis assay.
  • newly synthesized DNA may be labeled.
  • 3 H- thymidine (approximately 10/xCi/ml) may be added to the cell culture media for a short period of time (1 hour, for example) .
  • Other labels may be utilized as well, including but not limited to biotinylated thymidine, fluorescently-labeled thymidine, or digoxigenin- labeled thymidine.
  • cells may be harvested, rinsed with phosphate buffered saline (PBS) and cold 0.3M perchloric acid (HC10 4 ) to extract unincorporated thymidine pools, and the amount of label incorporated into newly synthesized DNA may be measured using techniques well known to those of skill in the art.
  • PBS phosphate buffered saline
  • HC10 4 cold 0.3M perchloric acid
  • DNA labeled with 3 H-thymidine may be obtained by determining the level of 3 H- radioactivity present in harvested cells' DNA.
  • Changes in a culture's ECM composition may be assayed in a variety of ways. For example, a determination of the total amount of collagen present may be made. In one such technique, utilized by Peterkofsky, B. and Diegelmann, R. (1971, Biochemistry i_:988-994) which is incorporated herein by reference in its entirety, cells are incubated in fresh media for 24 hours prior to being placed in serum-free media containing B-aminoproprionitrile (BAPN) , a collagen crosslinking inhibitor, and 3 H-proline (2.5 ⁇ Ci/ml). Total collagen amounts may then be estimated in the culture medium and the cell layer as collagenase sensitive material. Such measurements are taken over various time periods.
  • BAPN B-aminoproprionitrile
  • 3 H-proline 2.5 ⁇ Ci/ml
  • chondrocyte cells may be labeled for 24 hours with 1.5 ⁇ Ci/ml of 3 H-proline in serum-free media, at which time the cells are rinsed with PBS and disintegrated using ultrasonication. Samples are then dialyzed against ImM ammonium bicarbonate (pH 7.5) for 72 hours and lyophilized. Samples may then be analyzed by one- or two- dimensional polyacrylamide gel electrophoresis, and the labeled collagens may be identified by fluorography, using standard techniques well known to those of ordinary skill in the art.
  • proteoglycan synthesis may be measured using a number of procedures. Using one such procedure, a chondrocyte cell culture may be labeled for 24 hours. This label may include, but is not limited to 35 S-sulfate (at a concentration of approximately lO ⁇ Ci/ml) or C- 3 H-glucosamine (at a concentration of approximately 2.5 ⁇ Ci/ml). The rate of proteoglycan synthesis may be determined by then measuring the 35 S or 3 H incorporation into the GAG chains.
  • the radioactive GAGs present in the medium and cell layer may be extracted following pronase (type XIV, Sigma Chemical Co.) digestion, in the presence of a Tris-HCl 0.1 M buffer, pH 7.5, containing 0.005 M calcium chloride, for 48 hours at 50°C. GAGs are then purified by alternating precipitations with cetylpyridinium chloride and ethanol as described in Jouis, V. et al. (FEBS Lett. 186:233-240, 1985), which is incorporated by reference herein in its entirety. GAG radioactivity may then be measured using, for example, liquid scintillation counting methods which are well known to those of ordinary skill in the art.
  • proteoglycan synthesis may be measured by incubating chondrocytes in media containing [D-1- 14 C] glucosamine hydrochloride
  • Proteoglycan amounts may be measured by digesting chondrocytes according to the method of Oegema et al.. (Oegema, T.R. et al., 1981, J. Biol. Chem. 256:1015- 1022) , which is incorporated herein by reference in its entirety. Digestion may be performed for 18 hours at 56°C, after which time samples may be cooled and then frozen at -20°C until being assayed. Proteoglycan levels may be measured using a metachromatic dye such as 1, 9-dimethylene blue (Farndale et al.. 1982, Connect. Tiss. Res. 9.:247-248) and comparing the intensity of staining to a GAG or proteoglycan standard, such as a commercial preparation of chondroitin sulfate (Sigma Chemical Co.) .
  • a metachromatic dye such as 1, 9-dimethylene blue
  • chondrocytes may be stained, and proteoglycan-containing ECM material may be visualized, with a dye including, but not limited to alcian blue (pH 2.8; Sigma Chemical Co.).
  • the levels of various cellular factors within treated chondrocyte cultures may also be measured using, for example, standard ELISA immunoassay techniques which are well known to those of ordinary skill in the art.
  • the factors whose levels may be measured include, but are not limited to tissue inhibitors of metalloproteinases (TIMP1 and TIMP2) , plasminogen activator inhibitor (PAI-1) , tissue plasminogen activator (TPA) , interleukin 1 (IL-1) , and tumor necrosis factor (TNF) .
  • Candidate cartilage repair compounds may be tested for their ability to alleviate or prevent the onset of OA in animal models.
  • Normal and OA animals may be treated with candidate cartilage repair compounds.
  • the effects of treatment may be measured and compared to measurements derived from untreated normal and OA animals. Comparison of these measurements allows scoring of the effectiveness of the candidate compound in cartilage repair.
  • the observations and measurements that may be performed on animals after treatment are macroscopic and microscopic evaluations of cartilage tissue and measurements quanitating the synthesis of ECM components, such as collagen and/or proteoglycans.
  • chondrocyte cultures may be exposed to, for example, varying concentrations of interleukin-1-beta or retinoic acid.
  • the conditions for the latter may be found in Morales and Roberts (Morales, T.I. and Roberts, A.B., 1992, Arch. Biochem. Biophys. 293:79-84) . which is incorporated herein by reference in its entirety.
  • OA is experimentally induced by producing joint laxity through the sectioning of the anterior or cruciate ligament of the knee joint of the hind limb of an adult dog.
  • the compound may be modified according to techniques such as those described above, in Sections 4.1 and 4.2, and the modified compound(s) generated may subsequently be tested for its effectiveness in cartilage repair, alone and/or in conjunction with bioactive molecules of the type, for example, are described above, in Section 4.3.
  • selection-modification- selection may be utilized until a compound or compounds of the desired cartilage repair activity is obtained.
  • the individual, well defined components of the invention may be employed to repair damaged hard tissue, especially damaged cartilage tissue as can be observed in OA.
  • An effective amount of the well defined components of the invention would be introduced into a host such that they would contact the damaged tissue for a period of time sufficient to repair the damaged tissue.
  • the components of the invention may serve, to alleviate and possibly prevent a prevalent human disease. Because, in addition to being a prevalent medical disease of humans, OA represents a serious veterinary problem, especially in the race horse and companion dog segments, the components of the invention may also be useful in the treatment of OA in these animals as well as in humans.
  • the components of the invention may exert their effect by modulating elements of cartilage tissue metabolism.
  • Such elements include, but are not limited to, stimulation of chondrocyte cell division, control of chondrocyte collagen and/or proteoglycan secretion, generation of a favorable proteinase to proteinase inhibitor ratio within the tissue of interest, and regulation of the production of cellular factors such as growth factors.
  • the components of the invention may be prepared as injectable formulations.
  • the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. Injections may be local, with intraarticular administration into, or intramuscular administration adjacent to the diseased joint(s) of the OA individual.

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Abstract

L'invention concerne des composés individuels bien définis et leurs utilisations seuls ou combinés avec des molécules bioactives telles que des facteurs de croissance ou des inhibiteurs de la métalloprotéinase pour la réparation des dommages cartilagineux tels que ceux rencontrés dans l'ostéo-arthrite. Lesdits composés bien définis peuvent contenir, entre autres, des composants purifiés de la matrice extra-cellulaire, des dérivés de composants de la matrice extra-cellulaire et des imitateurs de glycosaminoglycane.
PCT/US1994/006490 1993-06-08 1994-06-08 Composes synthetiques et naturels purifies pour le traitement de l'osteo-arthrite WO1994028889A1 (fr)

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EP0959879A4 (fr) * 1996-10-10 2000-03-29 Gen Hospital Corp Therapie photodynamique pour le traitement de l'arthrose
WO2002047696A1 (fr) 2000-12-16 2002-06-20 Aventis Pharma Deutschland Gmbh Utilisation d'heparine de faible masse moleculaire pour le traitement de l'osteoarthrose
EP0957925A4 (fr) * 1996-12-13 2002-07-24 Lescarden Inc Traitement de l'arthrose par administration de poly-n-acetyl-d-glucosamine
WO2003062457A1 (fr) * 2002-01-22 2003-07-31 Rush-Presbyterian-St. Luke's Medical Center Substitut cartilagineux pour la recherche medicamenteuse
WO2003009808A3 (fr) * 2001-07-24 2003-09-04 Univ Yale Procedes, compositions et necessaires relatifs a des molecules chitinases et de type chitinase ainsi qu'a des maladies inflammatoires
WO2001051054A3 (fr) * 2000-01-12 2003-10-30 Univ North Carolina Chapel Hill Utilisation de derives de cyclopentenone pour la regeneration osseuse et parodontale
US6716853B2 (en) 2002-03-02 2004-04-06 Aventis Pharma Deutschland Gmbh Cyclic N-substituted alpha-imino carboxylic acids for selective inhibition of collogenase
EP1476471A4 (fr) * 2002-01-23 2005-03-16 Inst Of Nutraceutical Res Pty Aliments fonctionnels pour le traitement, la protection et la restauration des tissus conjonctifs
EP0852236A4 (fr) * 1995-09-19 2005-06-01 Seikagaku Kogyo Co Ltd Agent anti-inflammatoire
FR2864090A1 (fr) * 2003-12-19 2005-06-24 Aventis Pharma Sa Derives carboxy-reduits de l'acide hyaluronique, leur preparation, leur application comme medicament et les compositions pharmaceutiques les renfermant
FR2864089A1 (fr) * 2003-12-19 2005-06-24 Aventis Pharma Sa Derives carboxy-reduits de la chondroitine sulfate, leur preparation, leur application comme medicament et les compositions pharmaceutiques les renfermant
FR2864087A1 (fr) * 2003-12-19 2005-06-24 Aventis Pharma Sa Derives carboxy-reduits du dermatan sulfate, leur preparation, leur application comme medicament et les compositions pharmaceutiques les renfermant
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US7799754B2 (en) 2004-10-14 2010-09-21 Biomimetic Therapeutics, Inc. Compositions and methods for treating bone
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WO1996016973A1 (fr) * 1994-12-01 1996-06-06 Seikagaku Corporation Fraction d'oligosaccharide de sulfate de keratane et medicament la contenant
EP0852236A4 (fr) * 1995-09-19 2005-06-01 Seikagaku Kogyo Co Ltd Agent anti-inflammatoire
EP0959879A4 (fr) * 1996-10-10 2000-03-29 Gen Hospital Corp Therapie photodynamique pour le traitement de l'arthrose
EP0957925A4 (fr) * 1996-12-13 2002-07-24 Lescarden Inc Traitement de l'arthrose par administration de poly-n-acetyl-d-glucosamine
WO1999003493A1 (fr) * 1997-07-14 1999-01-28 Meiji Milk Products Co., Ltd. Medicaments contenant midkine en tant principe actif ou inhibiteurs desdits medicaments
US7390491B2 (en) 1997-07-14 2008-06-24 Takashi Muramatsu Agents comprising midkine or an inhibitor thereof as active ingredient
WO2001051054A3 (fr) * 2000-01-12 2003-10-30 Univ North Carolina Chapel Hill Utilisation de derives de cyclopentenone pour la regeneration osseuse et parodontale
WO2002047696A1 (fr) 2000-12-16 2002-06-20 Aventis Pharma Deutschland Gmbh Utilisation d'heparine de faible masse moleculaire pour le traitement de l'osteoarthrose
WO2003009808A3 (fr) * 2001-07-24 2003-09-04 Univ Yale Procedes, compositions et necessaires relatifs a des molecules chitinases et de type chitinase ainsi qu'a des maladies inflammatoires
US8679503B2 (en) 2001-07-24 2014-03-25 Yale University Methods, compositions and kits relating to chitnases and chitnase-like molecules and inflammation disease
US7476257B2 (en) 2001-09-15 2009-01-13 Rush University Medical Center Methods to engineer stratified cartilage tissue
US6933298B2 (en) 2001-12-08 2005-08-23 Aventis Pharma Deutschland Gmbh Pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides and the use thereof for selectively inhibiting collagenases
WO2003062457A1 (fr) * 2002-01-22 2003-07-31 Rush-Presbyterian-St. Luke's Medical Center Substitut cartilagineux pour la recherche medicamenteuse
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US7371820B2 (en) 2002-01-23 2008-05-13 Institute Of Nutraceutical Research Pty Ltd. Nutraceuticals for the treatment, protection and restoration of connective tissues
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US7205315B2 (en) 2003-09-27 2007-04-17 Sanofi-Aventis Deutschland Gmbh Bicyclic imino acid derivatives as inhibitors of matrix metalloproteinases
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US10456450B2 (en) 2006-06-30 2019-10-29 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US8870954B2 (en) 2008-09-09 2014-10-28 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
US11135341B2 (en) 2008-09-09 2021-10-05 Biomimetic Therapeutics, Llc Platelet-derived growth factor composition and methods for the treatment of tendon and ligament injuries
US11235030B2 (en) 2010-02-22 2022-02-01 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies
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US9561260B2 (en) 2010-12-28 2017-02-07 Depuy Mitek, Llc Compositions for treating joints comprising bone morphogenetic protein and hyaluronic acid
US10227369B2 (en) 2013-03-12 2019-03-12 The Johns Hopkins University Short-chain fatty acid hexosamine analogs and their use in tissue engineering applications
WO2014164723A1 (fr) * 2013-03-12 2014-10-09 The Johns Hopkins University Analogues hexosamine acide gras à chaîne courte et leur utilisation dans des applications en génie tissulaire
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