CN-122029281-A - Treatment of osteoarthritis using procollagen galactosyltransferase 2 (COLGALT 2) inhibitors

Abstract

The present disclosure relates generally to treating a subject suffering from or at risk of developing osteoarthritis by administering to the subject an inhibitor of procollagen galactosyltransferase 2 (COLGALT 2).

Inventors

• J. Bovi En
• P. Dornbers
• L.A. Lota
• J. Raya Garcia Del Ormo
• B. Gerati
• J. Markini
• A. Barras
• M. HAAS

Assignees

• 瑞泽恩制药公司

Dates

Publication Date

20260512

Application Date

20241024

Priority Date

20231024

Claims (20)

1. 1. A method of treating a subject suffering from or at risk of developing osteoarthritis, the method comprising administering to the subject an inhibitor of procollagen galactosyltransferase 2 (COLGALT 2).
2. 2. The method of claim 1, wherein the COLGALT inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to a COLGALT2 nucleic acid molecule.
3. 3. The method of claim 2, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA).
4. 4. The method of claim 3, wherein the inhibitory nucleic acid molecule comprises siRNA.
5. 5. The method of claim 3, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.
6. 6. The method of any one of claims 1-5, wherein an osteoarthritis therapeutic agent or an osteoarthritis therapy is also administered to the subject.
7. 7. The method of any one of claims 1 to 6, further comprising detecting the presence or absence of COLGALT variant nucleic acid molecules in a biological sample from the subject.
8. 8. The method of claim 7, further comprising administering to the subject an osteoarthritis therapeutic agent or an osteoarthritis therapy in an amount that is the same as or less than a standard dose amount when the COLGALT variant nucleic acid molecule is not present in the biological sample.
9. 9. The method of claim 7, further comprising administering to the subject an osteoarthritis therapeutic agent or an osteoarthritis therapy in an amount that is the same as or less than a standard dose amount when the subject is heterozygous for the COLGALT variant nucleic acid molecule.
10. 10. The method of any one of claims 7 to 9, wherein the COLGALT variant nucleic acid molecule comprises a splice site variant, a stop codon acquisition variant, a start codon deletion variant, a stop codon deletion variant, a frameshift variant, a missense variant, an in-frame insertion deletion variant, and/or a variant encoding a truncated COLGALT variant polypeptide.
11. 11. The method of any one of claims 7 to 9, wherein the COLGALT variant nucleic acid molecule comprises any one or more of the genetic variations of the genomic nucleic acid molecules listed in table 4, or an mRNA molecule produced by the genomic nucleic acid molecule or a cDNA molecule produced by the mRNA molecule.
12. 12. A method of treating a subject suffering from or at risk of developing osteoarthritis by administering an osteoarthritis therapeutic agent or an osteoarthritis therapy, the method comprising: determining or having determined whether the subject has a procollagen galactosyltransferase 2 (COLGALT 2) variant nucleic acid molecule by: Obtaining or having obtained a biological sample from said subject, and Subjecting the biological sample to or having undergone sequence analysis to determine whether the subject has a genotype comprising a COLGALT variant nucleic acid molecule, and Administering or continuing to administer an amount of the osteoarthritis therapeutic agent or osteoarthritis therapy and/or COLGALT2 inhibitor that is the same as or less than the standard dose amount to a subject as COLGALT reference; Administering or continuing to administer the osteoarthritis therapeutic agent or osteoarthritis therapy and/or COLGALT2 inhibitor in an amount equal to or less than a standard dose amount to a subject heterozygous for the COLGALT variant nucleic acid molecule, or Administering or continuing to administer a standard dose of the osteoarthritis therapeutic agent or osteoarthritis therapy to a subject homozygous for the COLGALT variant nucleic acid molecule; wherein the presence of the COLGALT variant nucleic acid molecule is indicative of a reduced risk of the subject developing osteoarthritis.
13. 13. The method of claim 12, wherein the COLGALT inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to a COLGALT2 nucleic acid molecule.
14. 14. The method of claim 13, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and/or a short hairpin RNA (shRNA).
15. 15. The method of claim 14, wherein the inhibitory nucleic acid molecule comprises siRNA.
16. 16. The method of claim 14, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.
17. 17. The method of any one of claims 12 to 16, wherein the method comprises administering or continuing administration of the osteoarthritis therapeutic agent or osteoarthritis therapy and the COLGALT inhibitor to a subject heterozygous for the COLGALT variant nucleic acid molecule in an amount identical to or less than a standard dose amount.
18. 18. The method of any one of claims 12 to 16, wherein the method comprises administering or continuing administration of the osteoarthritis therapeutic agent or osteoarthritis therapy and the COLGALT2 inhibitor to a subject as a COLGALT reference in an amount that is the same as or less than a standard dose amount.
19. 19. The method of any one of claims 12 to 18, wherein the COLGALT variant nucleic acid molecule comprises a splice site variant, a stop codon acquisition variant, a start codon deletion variant, a stop codon deletion variant, a frameshift variant, a missense variant, an in-frame insertion deletion variant, and/or a variant encoding a truncated COLGALT variant polypeptide.
20. 20. The method of any one of claims 12 to 19, wherein the COLGALT variant nucleic acid molecule comprises any one or more of the genetic variations of the genomic nucleic acid molecules listed in table 4, or an mRNA molecule produced by the genomic nucleic acid molecule or a cDNA molecule produced by the mRNA molecule.

Description

Treatment of osteoarthritis using procollagen galactosyltransferase 2 (COLGALT 2) inhibitors Reference to sequence Listing The application includes a sequence listing submitted electronically as an XML file, named 381204327SEQ, created at 2024, 10, 24, size 2,481,246 bytes. The sequence listing is incorporated herein by reference. Technical Field The present disclosure relates generally to treating a subject suffering from or at risk of developing osteoarthritis by administering to the subject an inhibitor of procollagen galactosyltransferase 2 (COLGALT 2), and to methods of identifying a subject at increased risk of developing osteoarthritis. Background Osteoarthritis (OA) is the most common type of arthritis and affects millions of people worldwide. Osteoarthritis is a degenerative joint disease that affects all tissues in the joint. Injury to articular cartilage (the soft tissue layer covering the bone ends) occurs early in the disease and is considered the onset of irreversible joint injury. Although OA can involve any joint, the most commonly affected joints are the knee, hip, hand and spine. OA may be diagnosed by physical examination and may include imaging examination (X-rays) to assess severity, as well as laboratory examination (such as, for example, blood or urine examination and joint fluid analysis). Symptoms of OA include i) joint pain, ii) joint stiffness after waking or inactivity, iii) joint tenderness when slight pressure is applied to the joint or near the joint, iv) loss of mobility, v) a sense of friction (pop or click) with the joint, vi) possible formation of bony spurs around the affected joint, and vii) swelling (inflammation of the soft tissue around the joint). Risk factors for OA include i) older (e.g., the risk of OA increases with age), ii) obese (weight gain can put stress on weight-bearing joints and proteins produced by adipose tissue can cause deleterious inflammation of joints and their surroundings), iii) joint damage, iv) gender (women are more prone to develop OA), v) repeated stress on joints, vi) genetics, vii) skeletal deformity, and viii) some metabolic diseases (such as diabetes and hemochromatosis). COLGALT2 is encoded by the 108 kb gene located at 1q25.3. COLGALT2 protein is 626 amino acids long and is a 73 kDa beta-galactosyltransferase that transfers beta-galactose to the hydroxylysine residues of collagen. COLGALT2 are believed to be capable of effecting procollagen galactosyltransferase activity involved in collagenous fibrous tissue. In addition, COLGALT2 is predicted to be involved in collagen chain trimerization and extracellular matrix tissue pathways. Disclosure of Invention The present disclosure provides methods of treating a subject suffering from or at risk of developing OA comprising administering COLGALT inhibitor to the subject. The present disclosure also provides a method of treating a subject suffering from or at risk of developing OA by administering an OA therapeutic or OA therapy comprising determining or having determined whether the subject has a COLGALT variant nucleic acid molecule obtained or has obtained from the subject, and performing or having performed a sequence analysis on the biological sample to determine whether the subject has a genotype comprising a COLGALT variant nucleic acid molecule, and administering or continuing administration of an OA therapeutic or OA therapy in an amount equal to or less than the standard dose amount and/or administration of COLGALT inhibitor to the subject as a reference to COLGALT2, administering or continuing administration of an OA therapeutic or OA therapy in an amount equal to or less than the standard dose amount and/or administration of COLGALT inhibitor to the subject for a COLGALT variant nucleic acid molecule heterozygous for the subject, or administration or continuing administration of a standard dose amount of an OA therapeutic or OA therapy to the subject for a COLGALT variant nucleic acid molecule, wherein the presence of COLGALT variant nucleic acid molecule indicates a reduced risk of developing OA in the subject. The disclosure also provides a method of identifying a subject at increased risk of developing OA comprising determining or having determined the presence or absence of a COLGALT variant nucleic acid molecule in a biological sample obtained from the subject, wherein the subject is at increased risk of developing OA when the subject is a COLGALT2 reference, and the subject is at reduced risk of developing OA when the subject is heterozygous or homozygous for a COLGALT variant nucleic acid molecule. The present disclosure also provides OA therapeutics for use in treating or preventing OA in a subject having a COLGALT variant nucleic acid molecule. The disclosure also provides COLGALT inhibitors for use in treating or preventing OA in a subject that is COLGALT2 reference or heterozygous for a COLGALT2 variant nucleic acid molecule. Drawings Fig. 1 shows that rare encoding v