IL-8, IL-6, IL-1 Beta and TET2 and DNMT3A in Atherosclerosis

• US 20200131576A1
• Filed: 04/24/2018
• Published: 04/30/2020
• Est. Priority Date: 04/25/2017
• Status: Active Application

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Siddhartha, Jaiswal, Kathiresan, Sekar, Ebert, Benjamin
• Application Number:
  US16/606,928
• Publication Number:
  US 20200131576A1
• Time in Patent Office: Days
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The application presently discloses a method of treating atherosclerosis in a human subject comprising administering an effective amount of an IL-8 inhibitor, an IL-6 inhibitor, and/or an IL-1β inhibitor, wherein the subject has a TET2 and/or DNMT3A mutation thereby treating atherosclerosis. It also discloses a method for treating atherosclerosis in a human subject comprising sequencing at least a part of a genome comprising TET2 and/or DNMT3A of one or more cells in a blood sample of the subject; determining from the sequencing whether the subject has one or more mutations in TET2 and/or DNMT3A, if it is determined that the subject has at least one TET2 and/or DNMT3A mutation, administering an IL-8 inhibitor, an IL-6 inhibitor, and/or an IL-1β inhibitor to a subject to the subject thereby treating atherosclerosis.

Claims

1. A method of treating atherosclerosis in a human subject comprising administering an effective amount of at least one IL-8 inhibitor, IL-6 inhibitor, and/or IL-1β

inhibitor, wherein the subject has a TET2 mutation and/or a DNMT3A mutation, thereby treating atherosclerosis.

8. The method of claim 1, wherein the at least one TET2 and/or DNMT3A mutation comprises a frameshift mutation, nonsense mutation, missense mutation, or splice-site variant mutation.

9. The method of claim 1, wherein the at least one TET2 and/or DNMT3A mutation comprises at least one loss-of-function TET2 and/or DNMT3A mutation.

10. The method of claim 8, wherein the mutation in TET2 results in an amino acid change in TET2 chosen from S145N, S282F, A308T, N312S, L346P, P399L, S460F, D666G, S817T, P941S, C1135Y, R1167T, I1175V, S1204C, R1214W, D1242R, D1242V, Y1245S, R1261C, R1261H, R1261L, F1287L, W1291R, K1299E, K1299N, R1302G, E1318G, P1367S, C1396W, L1398R, V1417F, G1869W, L1872P, I1873T, C1875R, H1881Q, H1881R, R1896M, R1896S, S1898F, V1900A, G1913D, A1919V, R1926H, P1941S, P1962L, R1966H, R1974M, and R2000K.

11. The method of claim 8, wherein the mutation in DNMT3A results in an amino acid change in DNMT3A chosen from F290I, F290C, V296M, P307S, P307R, R326H, R326L, R326C, R326S, G332R, G332E, V339A, V339M, V339G, L344Q, L344P, R366P, R366H, R366G, A368T, A368V, R379H, R379C, I407T, I407N, I407S, F414L, F414S, F414C, A462V, K468R, C497G, C497Y, Q527H, Q527P, Y533C, S535F, C537G, C537R, G543A, G543S, G543C, L547H, L547P, L547F, M548I, M548K, G550R, W581R, W581G, W581C, R604Q, R604W, R635W, R635Q, S638F, G646V, G646E, L653W, L653F, I655N, V657A, V657M, R659H, Y660C, V665G, V665L, M674V, R676W, R676Q, G685R, G685E, G685A, D686Y, D686G, R688H, G699R, G699S, G699D, P700L, P700S, P700R, P700Q, P700T, P700A, D702N, D702Y, V704M, V704G, I705F, I705T, I705S, I705N, G707D, G707V, C710S, C710Y, S714C, V716D, V716F, V716I, N717S, N717I, P718L, R720H, R720G, K721R, K721T, Y724C, R729Q, R729W, R729G, F731C, F731L, F731Y, F731I, F732del, F732C, F732S, F732L, E733G, E733A, F734L, F734C, Y735C, Y735N, Y735S, R736H, R736C, R736P, L737H, L737V, L737F, L737R, A741V, P742P, P743R, P743L, R749C, R749L, R749H, R749G, F751L, F751C, F752del, F752C, F752L, F752I, F752V, W753G, W753C, W753R, L754P, L754R, L754H, F755S, F755I, F755L, M761I, M761V, G762C, V763I, S770L, S770W, S770P, R771Q, F772I, F772V, L773R, L773V, E774K, E774D, E774G, I780T, D781G, R792H, W795C, W795L, G796D, G796V, N797Y, N797H, N797S, P799S, P799R, P799H, R803S, R803W, P804L, P804S, K826R, S828N, K829R, T835M, N838D, K841Q, Q842E, P849L, D857N, W860R, E863D, F868S, G869S, G869V, M880V, S881R, S881I, R882H, R882P, R882C, R882G, A884P, A884V, Q886R, L889P, L889R, G890D, G890R, G890S, V895M, P896L, V897G, V897D, R899L, R899H, R899C, L901R, L901H, P904L, F909C, P904Q, A910P, C911R, C911Y.

12. The method of claim 1, wherein the human subject has at least one somatic blood cell clone with one mutant TET2 allele and one wildtype TET2 allele.

13. The method of claim 1, wherein the human subject has at least one somatic blood cell clone with two mutant TET2 alleles.

14. The method of claim 1, wherein the human subject has at least one somatic blood cell clone with one mutant DNMT3A allele and one wildtype DNMT3A allele.

15. The method of claim 1, wherein the human subject has at least one somatic blood cell clone with two mutant DNMT3A alleles.

16. The method of claim 1, wherein the human subject has clonal hematopoiesis of indeterminate potential (CHIP).

17. The method of claim 1, wherein the human subject has at least one TET2 and/or DNMT3A mutation with a variant allele fraction of at least 2%, 5%, 10%, 13.5%, 15%, 20%, 25%, 27%, 30%.

18. The method of claim 1, wherein the subject'"'"'s plasma level of IL-8 is at least 25 ng/mL, 30 ng/mL, 40 ng/mL, 45 ng/mL, 50 ng/mL, 55 ng/mL, 60 ng/mL, 65 ng/mL, 70 ng/mL, 75 ng/mL, or 80 ng/mL.

19. The method of claim 1, wherein a TET2 and/or DNMT3A mutation is identified by whole exome sequencing (WES).

20. The method of claim 1, wherein a TET2 and/or DNMT3A mutation is identified by sequencing DNA.

2. A method for treating atherosclerosis in a human subject comprising:

a. sequencing at least a part of a genome comprising TET2 and/or DNMT3A of one or more cells in a blood sample of the subject;

b. determining from the sequencing whether the subject has one or more mutations in TET2 and/or DNMT3A, and

c. if it is determined that the subject has at least one TET2 and/or DNMT3A mutation, administering at least one IL-8 inhibitor, IL-6 inhibitor, and/or IL-1β

inhibitor to a subject to the subject thereby treating atherosclerosis.

3. A method of treating atherosclerosis in a human subject comprising administering an effective amount of at least one IL-8 inhibitor, wherein the subject'"'"'s plasma IL-8 level is at least 20 ng/mL thereby treating atherosclerosis.

4. A method for treating atherosclerosis in a human subject comprising:

a. determining from a plasma sample whether the subject has an increased level of plasma IL-8, and

b. if it is determined that the subject has an IL-8 level of at least 20 ng/mL, administering an effective amount of at least one IL-8 inhibitor to a subject to the subject thereby treating atherosclerosis.

5. (canceled)

6. (canceled)

7. (canceled)