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Last Updated: March 28, 2024

Claims for Patent: 7,867,727


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Summary for Patent: 7,867,727
Title:Methods and reagents for treatment and diagnosis of vascular disorders and age-related macular degeneration
Abstract: Disclosed are screening methods for determining a human subject\'s propensity to develop a vascular disorder and/or age-related macular degeneration (AMD), therapeutic or prophylactic compounds for treating disease or inhibiting its development, and methods of treating patients to alleviate symptoms of the disease, prevent or delay its onset, or inhibit its progression. The inventions are based on the discovery that persons with a genome having a deletion of the CFHR-1 and/or CFHR-3 gene, which normally lie on human chromosome 1 between DNA encoding CFH and CFHR-4, are at reduced risk of developing AMD, and elevated risk of developing vascular disease such as aneurysm.
Inventor(s): Hageman; Gregory S. (Coralville, IA)
Assignee: University of Iowa Research Foundation (Iowa City, IA)
Application Number:11/894,667
Patent Claims:1. A screening method for determining a human subject's propensity to develop an abdominal aortic aneurysm and/or age-related macular degeneration (AMD) comprising: analyzing a biological sample from the subject to detect the presence or absence of a deletion of at least 1000 bp in the region of chromosome 1 between the 3' end of exon 22 of the complement factor H (CFI-1) gene and the 5' end of exon 1 of complement Factor H-related 4 (CFHR4) gene wherein the presence of a deletion indicates the subject is at increased risk of developing an abdominal aortic aneurysm and is at decreased risk of developing AMD.

2. The method of claim 1 wherein the presence or absence of the deletion is detected by assaying for a gene product encoded in chromosome 1 between the 3' end of exon 22 of the complement factor H (CFH) gene and the 5' end of exon 1 of complement Factor H-related 4 (CFHR4) gene, where the absence of the gene product, or a reduced level of expression of the gene product, indicates the presence of deletion.

3. The method of claim 2 wherein the presence or absence of a complement Factor H-related 1 (CFHR1) gene product and/or a complement Factor H-related 3 (CFHR3) gene product is detected, where the absence of a gene product is indicative of a deletion.

4. The method of claim 2 wherein the gene product is a protein.

5. The method of claim 3 wherein entire protein coding region of the CFHR3 gene is deleted.

6. The method of claim 3 wherein entire protein coding region of the CFHR1 gene is deleted.

7. The method of claim 1 comprising detecting a deletion of an intragenic sequence selected from a sequence between the CFHR3 gene and the CFHR1 gene and a sequence between the CFHR1 gene and the CFHR4 gene.

8. The method of claim 1 wherein the subject is homozygous for the deletion.

9. The method of claim 1 wherein the biological sample is blood, serum, urine or a tissue sample.

10. The method of claim 4 wherein the detection step comprises detecting a gene product using an immunoassay or mass spectroscopy.

11. The method of claim 1 wherein the presence or absence of the deletion is detected by assaying for a truncated CFHR1 or CFHR3 gene product, where detection of a truncated gene product is indicative of a deletion.

12. The method of claim 1 wherein the step comprising detecting the presence or absence of a deletion is performed by analyzing a chromosome or nucleic acid from the subject.

13. The method of claim 12 wherein the nucleic acid is DNA or RNA.

14. The method of claim 1 wherein the subject has a genotype of T at position 1277 of the coding region of the CFH gene of the chromosome comprising the deletion.

15. The method of claim 1 further comprising detecting genetic variants of complement factor H (CFH) gene comprising detecting one or a plurality of polymorphic sites selected from the group consisting of: a) any one or more of rs529825; rs800292; rs3766404; rs1061147; rs1061170; and rs203674; b) any one of more of intron 2 (IVS2 or insTT); rs2274700; exon 10A; and rs375046; c) one or both of rs529825 and rs800292; d) one or more of rs1061147, rs1061170 and rs203674; e) at least one of rs529825 and rs800292; and rs3766404; and at least one of rs1061147, rs1061170 and rs203674; f) at least rs529825, rs800292, rs3766404, rs1061170, and rs203674; g) exon 22 (R1210C); and h) exon 22 (R1210C) and any of (a)-(g).

16. The method of claim 1 further comprising detecting in a sample from the subject a macular degeneration-associated molecule selected from the group consisting of fibulin-3, vitronectin, .beta.-crystallin A2, .beta.-crystallin A3, .beta.-crystallin A4, .beta.-crystallin S, glucose-regulated protein 78 kD (GRP-78), calreticulin, 14-3-3 protein epsilon, serotransferrin, albumin, keratin, pyruvate carboxylase, villin 2, complement 1 q binding protein/hyaluronic acid binding protein ("complement 1 q component"), amyloid A (a1 amyloid A), amyloid P component, C5 and CSb-9 terminal complexes, HLA-DR, fibrinogen, Factor X, prothrombin, complements 3,5 and 9, complement reactive protein (CRP), HLA-DR, apolipoprotein A, apolipoprotein E, antichymotrypsin, p2 microglobulin, thrombospondin, elastin, collagen, ICAM-1, LFA1, LFA3, B7, IL-1, IL-6, IL-12, TNF-alpha, GM-CSF, heat shock proteins, colony stimulating factors (GM-CSF, M-CSFs), and IL-10.

17. The method of claim 1 further comprising detecting in a sample from the subject genetic variants of the HTRA1 gene comprising detecting a polymorphic site selected from the group consisting of: at least one of rs10490924, rs11200638, rs760336, and rs763720.

18. The method of claim 1 further comprising detecting in a sample from the subject genetic variants of the complement factor B (BF) gene and/or the complement component 2 (C2) gene comprising detecting a polymorphic site selected from the group consisting of: a) A or G at rs641153 of the BF gene, or R or Q at position 32 of the BF protein; b) A or T at rs4151667 of the BF gene, or L or H at position 9 of the BF protein; c) G or T at rs547154 of the C2 gene; and d) C or G at rs9332379 of the C2 gene, or E of D at position 318 of the C2 protein.

19. The method of claim 1 wherein the entire protein coding region of the CFHR3 gene is deleted.

20. The method of claim 1 wherein the entire protein coding region of the CFHR1 gene is deleted.

21. The method of claim 1 wherein the subject has a deletion of at least 10,000 bp in the genomic sequence encoding CFHR1 and/or CFHR3.

22. The method of claim 21 wherein the entire genomic sequence encoding CFHR3 is deleted.

23. The method of claim 21 wherein the entire genomic sequence encoding CFHR1 is deleted.

24. The method of claim 21 wherein at least a portion of the genomic sequence encoding CFHR1 and at least a portion of the genomic sequence encoding CFHR3 is deleted.

25. A screening method for determining a human subject's propensity to develop age-related macular degeneration (AMD) and/or abdominal aortic aneurysm (AAA) comprising analyzing the subject's genome to detect the presence or absence of a deletion of at least 10,000 bp in the genomic sequence encoding CFHR1 and/or CFHR3, wherein the presence of said deletion indicates the subject is at increased risk of developing an abdominal aortic aneurysm and is at decreased risk of developing AMD.

26. The method of claim 25 wherein the entire genomic sequence encoding CFHR3 is deleted.

27. The method of claim 25 wherein the entire genomic sequence encoding CFHR1 is deleted.

28. The method of claim 25 wherein at least a portion of the genomic sequence encoding CFHR1 and at least a portion of the genomic sequence encoding CFHR3 is deleted.

29. The method of claim 26 wherein the subject is homozygous for said deletion.

30. The method of claim 4 wherein the protein is CFHR1.

Details for Patent 7,867,727

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 06/04/1986 ⤷  Try a Trial 2026-07-13
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 ⤷  Try a Trial 2026-07-13
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b Injection 103132 ⤷  Try a Trial 2026-07-13
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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