Methods Of Treating A Metabolic Disorder With Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) Inhibitors

Abstract

The present disclosure provides methods of treating a subject having a metabolic disorder or is at risk of developing a metabolic disorder or preventing a subject from developing a metabolic disorder, and methods of identifying subjects having an increased risk of developing a metabolic disorder.

Claims

1. A method of treating a subject having a metabolic disorder or at risk of developing a metabolic disorder, the method comprising administering a Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) inhibitor to the subject.

2. The method according to claim 1, wherein the metabolic disorder is Type-2 diabetes, increased hemoglobin A1c, or increased serum glucose.

3-4. (canceled)

5. The method according to claim 1, wherein the MAP3K15 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to a MAP3K15 nucleic acid molecule.

6. The method according to claim 5, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

7-12. (canceled)

13. The method according to claim 1, further comprising detecting the presence or absence of a MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15 predicted loss-of-function polypeptide in a biological sample from the subject.

14. The method according to claim 13, further comprising administering a therapeutic agent that treats or prevents the metabolic disorder in a standard dosage amount to a subject wherein the MAP3K15 missense variant nucleic acid molecule is absent from the biological sample.

15. The method according to claim 13, further comprising administering a therapeutic agent that treats or prevents the metabolic disorder in a dosage amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the MAP3K15 missense variant nucleic acid molecule.

16. The method according to claim 13, wherein the MAP3K15 predicted missense variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, or an in-frame indel variant, or a variant that encodes a truncated MAP3K15 predicted loss-of-function polypeptide.

17. The method according to claim 16, wherein the MAP3K15 missense variant nucleic acid molecule encodes a truncated MAP3K15 predicted loss-of-function polypeptide.

18. A method of treating a subject with a therapeutic agent that treats or prevents a metabolic disorder, wherein the subject has a metabolic disorder or is at risk of developing a metabolic disorder, the method comprising the steps of: determining whether the subject has a Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) missense variant nucleic acid molecule encoding a MAP3K15 predicted loss-of-function polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the MAP3K15 missense variant nucleic acid molecule; and administering or continuing to administer the therapeutic agent that treats or prevents the metabolic disorder in a standard dosage amount to a subject that is MAP3K15 reference, and/or administering a MAP3K15 inhibitor to the subject; administering or continuing to administer the therapeutic agent that treats or prevents the metabolic disorder in an amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the MAP3K15 missense variant nucleic acid molecule, and/or administering a MAP3K15 inhibitor to the subject; or administering or continuing to administer the therapeutic agent that treats or prevents the metabolic disorder in an amount that is the same as or less than a standard dosage amount to a subject that is homozygous for the MAP3K15 missense variant nucleic acid molecule; wherein the presence of a genotype having the MAP3K15 missense variant nucleic acid molecule encoding the MAP3K15 predicted loss-of-function polypeptide indicates the subject has a decreased risk of developing the metabolic disorder.

19. The method according to claim 18, wherein the subject is MAP3K15 reference, and the subject is administered or continued to be administered the therapeutic agent that treats or prevents the metabolic disorder in a standard dosage amount, and is administered a MAP3K15 inhibitor.

20. The method according to claim 18, wherein the subject is heterozygous for a MAP3K15 missense variant nucleic acid molecule, and the subject is administered or continued to be administered the therapeutic agent that treats or prevents the metabolic disorder in an amount that is the same as or less than a standard dosage amount, and is administered a MAP3K15 inhibitor.

21. The method according to claim 18, wherein the MAP3K15 missense variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, or an in-frame indel variant, or a variant that encodes a truncated MAP3K15 predicted loss-of-function polypeptide.

22. The method according to claim 18, wherein the MAP3K15 missense variant nucleic acid molecule encodes a truncated MAP3K15 predicted loss-of-function polypeptide.

23. The method according to claim 18, wherein the MAP3K15 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to a MAP3K15 nucleic acid molecule.

24. The method according to claim 23, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

25-30. (canceled)

31. The method according to claim 18, wherein the metabolic disorder is Type-2 diabetes.

32. The method according to claim 18, wherein the metabolic disorder is increased hemoglobin A1c.

33. The method according to claim 18, wherein the metabolic disorder is increased serum glucose.

34. The method according to claim 18, wherein the metabolic disorder is Type-2 diabetes, and the therapeutic agent is chosen from metformin, an insulin, a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, a GLP-1 receptor agonist, and an SGLT2 inhibitor, or any combination thereof.

35. The method according to claim 18, wherein the metabolic disorder is Type-2 diabetes, and therapeutic agent is chosen from metformin, insulin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin, or any combination thereof.

36-73. (canceled)

Description

EXAMPLES

Example 1: Novel Association Between MAP3K15 and Protection from Type-2 Diabetes

[0138] The exomes of 454,787 UKB study participants were sequenced, with 95.8% of targeted bases covered at a depth of 20× or greater, as previously described (Szustakowski, Advancing Human Genetics Research and Drug Discovery through Exome Sequencing of the UK Biobank. bioRxiv, 2021; and Van Hout et al., Nature, 2020). Twelve million variants were identified in 39 million base pairs across the coding regions of 18,659 genes (data not shown). Among the variants identified were 3,375,252 (median of 10,260 per individual) synonymous, 7,689,495 (9,284 per individual) missense and 889,957 (212 per individual) putative loss-of-function (pLOF) variants (data not shown), of which about half were observed only once in this dataset (singleton variants; data not shown).

[0139] A novel association was discovered between a burden of predicted loss-of-function (pLOF) and deleterious missense variants in MAP3K15 and both lower levels of hemoglobin A1c (7,551 carriers; effect=−0.09 SD, 95% CI −0.10 to −0.073, P=2×10.sup.−31) and lower serum glucose (6,885 carriers; effect=−0.090, 95% CI −0.110 to −0.073, P=1.7×10.sup.−25). In addition, a burden of pLOFs and deleterious missense variants in MAP3K15 was also associated with protection from Type-2 diabetes (7,863 carriers; OR=0.80, 95% CI 0.74 to 0.87, P=1×10.sup.−2). Furthermore, there was supporting evidence in a GHS study (a health system-based cohort from central and eastern Pennsylvania (USA) with ongoing recruitment since 2006) for all three phenotypes: hemoglobin A1c (1,304 carriers; effect=−0.040 SD units, 95% CI −0.079 to −0.002, P=0.038), glucose (1,754 carriers; effect=−0.097 SD units, 95% CI −0.130 to −0.064, P=1.3×10.sup.−8) and type-2 diabetes (2,455 carriers; OR=0.91, 95% CI 0.84 to 0.98, P=0.018).

[0140] Various modifications of the described subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, U.S. and non-U.S. patents, patent application publications, international patent application publications, gene bank accession numbers, and the like) cited in the present application is incorporated herein by reference in its entirety and for all purposes.