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EP-4739330-A1 - CONSENSUS PEPTIDES IN HYA FOR USE IN TREATING DEGENERATED JOINTS

EP4739330A1EP 4739330 A1EP4739330 A1EP 4739330A1EP-4739330-A1

Abstract

Pharmaceutical formulations are described for use in medicine, in particular for preventing, ameliorating, preventing progression of and/or treating arthritis, comprising artificial peptides characterized by a proline sequence prevalent in key matricellular proteins that partake in wound healing as well as in bone and cartilage formation and connective tissue maintenance in all vertebrates. The current invention relates to a pharmaceutical formulation in the form of a gel comprising a. an artificial peptide comprising the amino acid sequence of Pro-X-X-Pro-Y- Y-Y-Pro-X-X-Pro-Y-Y-Pro-X-X-Pro-X- Pro-Y-Y-Y-Y-Y-Y-Pro-Y-Y-Y-Y-Y-Y-Pro-X-X-Pro-X- Pro-Y-Y-Y-Pro-Y-Y-Pro-Y-Pro-X-X-Pro-Y-Pro-Y-Y-Pro-X-X- Pro-Y-Y-Pro-X-X-Pro-Y-Y- Pro-X-X-Pro-Y-Pro-Pro-X-Pro-Pro-X-X-X-X-X-X-X-X-Pro-X-X-Pro-X-X-X-X (SEQ ID NO 1 ) and/or an artificial peptide comprising or consisting of the amino acid sequence of Pro-X-X-Pro-Y-Y-Pro-X-X-Pro-Y-Y- Pro-X-X-Pro-Y-Y- Pro-Y-Pro-Pro-X-Pro-Pro (SEQ ID NO 2), wherein i) Pro is proline; ii) X is an amino acid selected from the group consisting of Ala, lie, Leu, Met, Phe, Trp and Vai; iii) Y is an amino acid selected from the group consisting of Asn, Cys, Gin, Ser, Thr and Tyr, b. cross-linked Hyaluronicfibres (HA-XL), and c. linear hyaluronic acid fibres (HA), for use in treating inflamed, degenerated and/or damaged joints.

Inventors

  • ØVREBØ, Øystein
  • ZAIDI, Rija Fatima
  • PERALE, GIUSEPPE
  • DE LAURETIS, Angela
  • LYNGSTADAAS, Ståle Petter

Assignees

  • NuPep AS

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1 . A pharmaceutical formulation in the form of a gel comprising a. an artificial peptide comprising, or consisting of, the amino acid sequence: Pro-X-X-Pro-Y-Y-Y-Pro-X-X-Pro-Y-Y-Pro-X-X-Pro-X- Pro-Y-Y-Y-Y-Y-Y- Pro-Y-Y-Y-Y-Y-Y-Pro-X-X-Pro-X-Pro-Y-Y-Y-Pro-Y-Y-Pro-Y-Pro-X-X-Pro-Y- Pro-Y-Y-Pro-X-X- Pro-Y-Y-Pro-X-X-Pro-Y-Y-Pro-X-X-Pro-Y-Pro-Pro-X-Pro- Pro-X-X-X-X-X-X-X-X-Pro-X-X-Pro-X-X-X-X (SEQ ID NO 1 ), wherein i) Pro is proline; ii) X is an amino acid selected from the group consisting of Ala, lie, Leu, Met, Phe, Trp and Vai; iii) Y is an amino acid selected from the group consisting of Asn, Cys, Gin, Ser, Thr and Tyr, and b. 1-40mg/mL linear hyaluronic acid fibres (HA) and 1-40 mg/mL cross-linked hyaluronic acid fibres (HA-XL), for use in treating an inflamed, degenerated and/or damaged joint.
  2. 2. A pharmaceutical formulation in the form of a gel comprising a. an artificial peptide comprising, or consisting of, the amino acid sequence: Pro-X-X-Pro-Y-Y-Pro-X-X-Pro-Y-Y- Pro-X-X-Pro-Y-Y- Pro-Y-Pro-Pro-X- Pro-Pro (SEQ ID NO 2), wherein i) Pro is proline; ii) X is an amino acid selected from the group consisting of Ala, lie, Leu, Met, Phe, Trp and Vai; and iii) Y is an amino acid selected from the group consisting of Asn, Cys, Gin, Ser, Thr and Tyr, and b. 1-40mg/mL linear hyaluronic acid fibres (HA) and 1-40 mg/mL cross-linked hyaluronic acid fibres (HA-XL), for use in treating an inflamed, degenerated and/or damaged joint.
  3. 3. A pharmaceutical formulation for use according to claim 1 or 2, wherein the artificial peptide is at least 90% identical to an artificial peptide selected from the group consisting of the amino acid sequences of SEQ ID NO 1 , SEQ ID NO 2, SEQ ID NO 3, SEQ ID NO 4, and SEQ ID NO 5, such as wherein the artificial peptide is one or more artificial peptide(s) selected from the group consisting of artificial peptides comprising the amino acid sequence of SEQ ID NO 4 and SEQ ID NO 5.
  4. 4. A pharmaceutical formulation for use according to any of the preceding claims, comprising a. 0.1-250 pg/mL, such as 0.1 , 1.0, 5.0, 10, 50, 100, 200 or 250 pg/mL of said artificial peptide, b. 1-40 mg/mL, such as1 .0, 2.5, 4, 10, 20, 25, 30 or 40 mg/mL cross-linked hyaluronic acid fibres (HA-XL), and c. 1-40 mg/mL, such as 1.0, 2.5, 4, 10, 20, 25, 30 or 40 mg/mL linear hyaluronic acid fibres (HA).
  5. 5. A pharmaceutical formulation for use according to any one of the preceding claims, wherein the cross-linked hyaluronic acid fibres (HA-XL) comprise or consist of 1 ,4-butanediol diglycidyl ether cross-linked hyaluronic acid fibres (HA- XL(BDDE)) and/or poly(ethylene glycol) diglycidyl ether (PEGDE) cross-linked hyaluronic acid fibres (HA-XL(PEGDE)).
  6. 6. A pharmaceutical formulation for use according to any of the preceding claims comprising a. 50 pg/mL of an artificial peptide with the amino acid sequence of SEQ ID NO 4 and/or SEQ ID NO 5, b. 20 mg/mL 1 ,4-butanediol diglycidyl ether cross-linked hyaluronic acid fibres (HA-XL(BDDE)) and/or poly(ethylene glycol) diglycidyl ether cross-linked hyaluronic acid fibres (HA-XL(PEGDE)), and c. 2.5 mg/mL linear hyaluronic acid fibres (HA).
  7. 7. A pharmaceutical formulation for use according to any of the preceding claims comprising a. 2 pg/mL of an artificial peptide with the amino acid sequence of SEQ ID NO 4 and/or SEQ ID NO 5, b. 20 mg/mL 1 ,4-butanediol diglycidyl ether cross-linked hyaluronic acid fibres (HA-XL(BDDE)) and/or poly(ethylene glycol) diglycidyl ether cross-linked hyaluronic acid fibres (HA-XL(PEGDE)), and c. 2.5 mg/mL linear hyaluronic acid fibres (HA).
  8. 8. A pharmaceutical formulation for use according to any of the preceding claims, wherein the hyaluronic acid fibres are between 0.7-4.0 MDa, such as between 1.0-2.0, between 1 .5-1 .8, or between 3.0-3.3 MDa, such as 1 ,5MDa.
  9. 9. A pharmaceutical formulation for use according to claim 6, 7 or 8, further comprising d. one or more buffering agent(s) e. one or more salt(s), and f. water.
  10. 10. A pharmaceutical formulation for use according to claim 6, 7 or 8, further comprising d. Water, e. Sodium Hydroxide, f. Sodium Chloride, g. Disodium Phosphate and h. Sodium Phosphate.
  11. 11 . A pharmaceutical formulation for use according to any of the preceding claims, wherein the artificial peptide is released at a controlled rate of 0.01-10 ug pr hour, such as about 0.01 , 0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 ug per hour.
  12. 12. A pharmaceutical formulation for use according to any of the preceding claims, wherein the pharmaceutical formulation induces and/or supports tissue healing and/or regeneration in a joint and/or in tissue adjacent to a joint.
  13. 13. A pharmaceutical formulation for use according to any of the preceding claims, wherein the pharmaceutical formulation reduces and/or suppresses an infection and/or inflammation in a joint and/or in tissue adjacent to a joint.
  14. 14. A pharmaceutical formulation for use according to any of the preceding claims, wherein the pharmaceutical formulation stimulates collagen production in joint tissue and/or promotes oriented collagen formation in joint tissue.
  15. 15. A pharmaceutical formulation for use according to any of the preceding claims, for use in preventing, ameliorating, preventing progression of and/or treating arthritis.
  16. 16. A pharmaceutical formulation for use according to any of the preceding claims, wherein the composition further comprises Mesenchymal Stromal Cell (MSC) cells.
  17. 17. A pharmaceutical formulation for use according to claim 16, wherein the composition comprises between 100.000-10.000.000 MSC cells pr. ml, preferably about 1.000.000 MSC cells pr. ml.
  18. 18. A pharmaceutical formulation for use according to any of the preceding claims, wherein the composition promotes MSC cell homing.
  19. 19. A pharmaceutical formulation for use according to any of the preceding claims, wherein the composition has anti-inflammatory properties.
  20. 20. A pharmaceutical formulation for use according to claim 19, wherein the antiinflammatory properties is measured by a reduction in proinflammatory cytokines.

Description

CONSENSUS PEPTIDES IN HYA FOR USE IN TREATING DEGENERATED JOINTS TECHNICAL FIELD The present invention relates to the field of tissue healing and/or regeneration for treating inflamed, degenerated and/or damaged joints. Pharmaceutical formulations are described comprising artificial peptides characterized by a proline sequence prevalent in key matricellular proteins that partake in wound healing as well as in bone and cartilage formation and connective tissue maintenance in all vertebrates and their uses in medicine. The artificial peptides are herein formulated in hydrogels, comprising linear hyaluronic acids and cross-linked hyaluronic acids for minimally invasive administration and/or controlled release, for use in the treatment of degenerative and/or inflammatory tissue conditions, damages, diseases and/or disorders in joints and/or ligaments, such as e.g., arthritis, rheumatoid arthritis and/or osteoarthritis. BACKGROUND Arthritis means inflammation or swelling of one or more joints. It describes more than 100 conditions that affect the joints, tissues around the joint, and other connective tissues. Specific symptoms vary depending on the type of arthritis, but usually include joint pain and stiffness. Osteoarthritis (OA) is the most common form of arthritis. Some people call it degenerative joint disease or “wear and tear” arthritis as it may arise from wear and tear on the joints, as well as genetic predisposition, joint injury or trauma. It occurs most frequently in the hands, hips, shoulders, elbows and knees, but is also often seen in fingers, wrists and toes. With OA, the cartilage within a joint begins to break down and the underlying bone begins to change. Rheumatoid arthritis, or RA, is an autoimmune and inflammatory disease, wherein the immune system attacks healthy cells in the body by mistake, causing inflammation in the affected parts of the body. RA mainly attacks the joints, usually many joints at once. In general, joints are the areas where two or more bones meet. Most joints are mobile, allowing the bones to move. Joints consist of cartilage, synovial membrane, ligaments, tendons, bursas and synovial fluid. Cartilage is composed of specialized cells called chondrocytes embedded within a matrix of collagen fibres and proteoglycans, and unlike bone, cartilage lacks blood vessels and nerves, which limits its ability to heal and regenerate. Cartilage covers the articulating surfaces of bones in joints, acting as a smooth and lubricated surface, where it reduces friction and absorbs shock during movement protecting bones from wear and tear. While cartilage has limited regenerative capacity, it can undergo repair to some extent. This process is slow and often results in the formation of fibrous scar tissue rather than the complete restoration of healthy cartilage. Degenerative and/or inflammatory tissue disorders, diseases and damages can affect all types of tissue in the joints. They can be caused by trauma, repeated trauma, infection, wear and tear, systemic disorders and autoimmune diseases. Disorders such as osteoporosis, rheumatoid arthritis, and osteoarthritis to some extend all lead to inflammation of the joints. Osteoarthritis occurs frequently in the aging population and varies in severity from mild inconveniences to severe disabling and incapacitating pain and joint stiffness, overall, severely affecting the quality of life for the patient. Biomaterial scientists design in particular organic bone substitutes based on the biochemical properties of the mimicked tissue to achieve near native functionality. Several non-collagenous proteins in bone are known as intrinsically disordered proteins (IDPs), as they lack detectible ordered domains and a fixed 3D structure under physiological conditions. EP2118136 discloses artificial IDPs peptides with improved properties for induction and/or stimulation of mineralization, in vivo and in vitro. Such peptides are provided which are easy to synthesize and methods of using the peptides for the induction and/or stimulation of mineral precipitation and/or biomineralization. The characterizing sequence of amino acids of the artificial peptides disclosed in EP2118136 is a proline rich sequence prevalent in key matricellular proteins that partake in wound healing as well as in bone and cartilage formation and connective tissue maintenance in all vertebrates. This core sequence of prolines is highly conserved in vertebrates, is intrinsically disordered and does not induce any immunogenic response in humans. Joint tissue healing remains challenging e.g., due to the limited blood-flow in some tissue, in particular cartilage. Thus, there is today still a largely unmet need for potent solutions for joint tissue healing and regeneration. In addition, because of the susceptibility of the tissue in the joint to develop post-surgery and/or post-treatment complications and disorders, it would be preferable to find ways for minimally invasive administration