Methods Of Treating Metabolic Disorders And Cardiovascular Disease With Inhibin Subunit Beta E (INHBE) Inhibitors

Abstract

The present disclosure provides methods of treating a subject having metabolic disorders and/or cardiovascular diseases, methods of identifying subjects having an increased risk of developing a metabolic disorder and/or a cardiovascular disease, and methods of detecting human Inhibin Subunit Beta E variant nucleic acid molecules and variant polypeptides.

1 . A method of treating a subject having or at risk of developing a metabolic disorder, type 2 diabetes, obesity, an elevated triglyceride level, lipodystrophy, liver inflammation, fatty liver disease, hypercholesterolemia, an elevated liver enzyme, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, cardiomyopathy, high blood pressure, and/or heart failure, the method comprising administering an Inhibin Subunit Beta E (INHBE) inhibitor to the subject. 
     
     
         2 - 14 . (canceled) 
     
     
         15 . The method according to  claim 1 , wherein the INHBE inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), ef a short hairpin RNA (shRNA) that hybridizes to an INHBE mRNA, or a Cas protein and guide RNA (gRNA) that hybridizes to a gRNA recognition sequence within an INHBE genomic nucleic acid molecule. 
     
     
         16 - 20 . (canceled) 
     
     
         21 . The method according to  claim 15 , wherein the gRNA recognition sequence comprises a nucleotide sequence according to any one of SEQ ID NOs:9-27. 
     
     
         22 . The method according to  claim 1 , further comprising detecting the presence or absence of an INHBE variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide in a biological sample from the subject. 
     
     
         23 . The method according to  claim 22 , wherein when the subject is INHBE reference, the subject is also administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases in a standard dosage amount, and when the subject is heterozygous or homozygous for an INHBE variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide, the subject is also administered a therapeutic agent that treats or inhibits metabolic disorders or cardiovascular diseases in a dosage amount that is the same as or lower than a standard dosage amount. 
     
     
         24 . (canceled) 
     
     
         25 . The method according to  claim 22 , wherein the INHBE variant nucleic acid molecule is a missense variant, 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 INHBE polypeptide. 
     
     
         26 - 33 . (canceled) 
     
     
         34 . A method of treating a subject with a therapeutic agent that treats or inhibits a metabolic disorder, wherein the subject is suffering from a metabolic disorder, the method comprising the steps of:
 determining whether the subject has an Inhibin Subunit Beta E (INHBE) variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide by:
 obtaining or having obtained a biological sample from the subject; and 
 performing or having performed a genotyping assay on the biological sample to determine if the subject has a genotype comprising the INHBE variant nucleic acid molecule; and 
   when the subject is INHBE reference, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the metabolic disorder in a standard dosage amount, and administering to the subject an INHBE inhibitor; and   when the subject is heterozygous for an INHBE variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the metabolic disorder in an amount that is the same as or lower than a standard dosage amount, and administering to the subject an INHBE inhibitor;   when the subject is homozygous for an INHBE variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the metabolic disorder in an amount that is the same as or lower than a standard dosage amount;   wherein the presence of a genotype having the INHBE variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide indicates the subject has a decreased risk of developing the metabolic disorder.   
     
     
         35 . The method according to  claim 34 , wherein the subject is INHBE reference, and the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the metabolic disorder in a standard dosage amount, and is administered an INHBE inhibitor. 
     
     
         36 . The method according to  claim 34 , wherein the subject is heterozygous for an INHBE variant nucleic acid molecule, and the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the metabolic disorder in an amount that is the same as or lower than a standard dosage amount, and is administered an INHBE inhibitor. 
     
     
         37 . A method of treating a subject with a therapeutic agent that treats or inhibits a cardiovascular disease, wherein the subject is suffering from a cardiovascular disease, the method comprising the steps of:
 determining whether the subject has an Inhibin Subunit Beta E (INHBE) variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide by:
 obtaining or having obtained a biological sample from the subject; and 
 performing or having performed a genotyping assay on the biological sample to determine if the subject has a genotype comprising the INHBE variant nucleic acid molecule; and 
   when the subject is INHBE reference, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the cardiovascular disease in a standard dosage amount, and administering to the subject an INHBE inhibitor; and   when the subject is heterozygous for an INHBE variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the cardiovascular disease in an amount that is the same as or lower than a standard dosage amount, and administering to the subject an INHBE inhibitor;   when the subject is homozygous for an INHBE variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the cardiovascular disease in an amount that is the same as or lower than a standard dosage amount;   wherein the presence of a genotype having the INHBE variant nucleic acid molecule encoding an INHBE predicted loss-of-function polypeptide indicates the subject has a decreased risk of developing the cardiovascular disease.   
     
     
         38 . The method according to  claim 37 , wherein the subject is INHBE reference, and the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the cardiovascular disease in a standard dosage amount, and is administered an INHBE inhibitor. 
     
     
         39 . The method according to  claim 37 , wherein the subject is heterozygous for an INHBE variant nucleic acid molecule, and the subject is administered or continued to be administered the therapeutic agent that treats or inhibits the cardiovascular disease in an amount that is the same as or lower than a standard dosage amount, and is administered an INHBE inhibitor. 
     
     
         40 - 45 . (canceled) 
     
     
         46 . The method according to  claim 34  or  claim 37 , wherein the INHBE variant nucleic acid molecule is a missense variant, 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 INHBE polypeptide. 
     
     
         47 - 52 . (canceled) 
     
     
         53 . The method according to  claim 34 , wherein the INHBE inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), ef a short hairpin RNA (shRNA) that hybridizes to an INHBE mRNA, or a Cas protein and guide RNA (gRNA) that hybridizes to a gRNA recognition sequence within an INHBE genomic nucleic acid molecule. 
     
     
         54 - 59 . (canceled) 
     
     
         60 . The method according to  claim 34 ,
 wherein the metabolic disorder is type 2 diabetes, and the therapeutic agent is chosen from metformin, insulin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, thiazolidinediones, rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin, or any combination thereof;   wherein the metabolic disorder is obesity, and the therapeutic agent is chosen from orlistat, phentermine, topiramate, bupropion, naltrexone, and liraglutide, or any combination thereof:   wherein the metabolic disorder is elevated triglyceride, and the therapeutic agent is chosen from rosuvastatin, simvastatin, atorvastatin, fenofibrate, gemfibrozil, fenofibric acid, niacin, and an omega-3 fatty acid, or any combination thereof,   wherein the metabolic disorder is lipodystrophy, and the therapeutic agent is chosen from tesamorelin, metformin, poly-L-lactic acid, calcium hydroxyapatite, polymethylmethacrylate, bovine collagens, human collagens, silicone, and hyaluronic acid, or any combination thereof;   wherein the metabolic disorder is liver inflammation, and the therapeutic agent is a hepatitis therapeutic or a hepatitis vaccine;   wherein the metabolic disorder is fatty liver disease include, and the subject is administered bariatric surgery and/or dietary intervention;   wherein the metabolic disorder is hypercholesterolemia, and the therapeutic agent is chosen from: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin calcium, simvastatin, cholestyramine, colesevelam, and colestipol, alirocumab, evolocumab, niaspan, niacor, fenofibrate, gemfibrozil, and bempedoic, or any combination thereof;   wherein the metabolic disorder is an elevated liver enzyme), and the therapeutic agent is chosen from coffee, folic acid, potassium, vitamin B6, a statin, and fiber, or any combination thereof; and   wherein the metabolic disorder is nonalcoholic steatohepatitis (NASH) and the therapeutic agent is obeticholic acid, Selonsertib, Elafibranor, Cenicriviroc, GR MD 02, MGL 3196, IMM124E, arachidyl amido cholanoic acid, GS0976, Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN 001, LMB763, BI 1467335, MSDC 0602, PF 05221304, DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide, GRI 0621, EYP001, VK2809, Nalmefene, LIK066, MT 3995, Elobixibat, Namodenoson, Foralumab, SAR425899, Sotagliflozin, EDP 305, Isosabutate, Gemcabene, TERN 101, KBP 042, PF 06865571, DUR928, PF 06835919, NGM313, BMS 986171, Namacizumab, CER 209, ND L02 s0201, RTU 1096, DRX 065, IONIS DGAT2Rx, INT 767, NC 001, Seladepar, PXL770, TERN 201, NV556, AZD2693, SP 1373, VK0214, Hepastem, TGFTX4, RLBN1127, GKT 137831, RYI 018, CB4209-CB4211, and JH 0920.   
     
     
         61 - 75 . (canceled) 
     
     
         76 . The method according to  claim 37 ,
 wherein the cardiovascular disease is high blood pressure, and the therapeutic agent is chosen from chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, perindopril, quinapril hydrochloride, ramipril, trandolapril, candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, valsartan, amlodipine besylate, bepridil, diltiazem hydrochloride, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil hydrochloride, doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride, methyldopa, carvedilol labetalol hydrochloride, alpha methyldopa, clonidine hydrochloride, guanabenz acetate, guanfacine hydrochloride, guanadrel, guanethidine monosulfate, reserpine, hydralazine hydrochloride, and minoxidil, or any combination thereof,.   wherein the cardiovascular disease is cardiomyopathy, and the therapeutic agent is an ACE inhibitor, an angiotensin II receptor blocker, a beta blocker, a calcium channel blocker, digoxin, an antiarrhythmic, an aldosterone blocker, a diuretic, an anticoagulant, a blood thinner, and a corticosteroid, and   wherein the cardiovascular disease is heart failure, and the therapeutic agent is an ACE inhibitor, an angiotensin-2 receptor blocker, a beta blocker, a mineralocorticoid receptor antagonist, a diuretic, ivabradine, sacubitril valsartan, hydralazine with nitrate, and digoxin.   
     
     
         77 - 160 . (canceled) 
     
     
         161 . The method according to  claim 37 , wherein the INHBE variant nucleic acid molecule is a missense variant, 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 INHBE polypeptide. 
     
     
         162 . The method according to  claim 37 , wherein the INHBE inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), a short hairpin RNA (shRNA) that hybridizes to an INHBE mRNA, or a Cas protein and guide RNA (gRNA) that hybridizes to a gRNA recognition sequence within an INHBE genomic nucleic acid molecule.