US 11,771,659 B2
Treating disease and promoting weight loss by inhibiting the TMA/FMO3/TMAO pathway
Stanley L. Hazen, Pepper Pike, OH (US); and Jonathan Mark Brown, Cleveland, OH (US)
Assigned to The Cleveland Clinic Foundation, Cleveland, OH (US)
Appl. No. 16/624,389
Filed by The Cleveland Clinic Foundation, Cleveland, OH (US)
PCT Filed Jun. 19, 2018, PCT No. PCT/US2018/038322
§ 371(c)(1), (2) Date Dec. 19, 2019,
PCT Pub. No. WO2018/236899, PCT Pub. Date Dec. 27, 2018.
Claims priority of provisional application 62/521,872, filed on Jun. 19, 2017.
Prior Publication US 2020/0121615 A1, Apr. 23, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/045 (2006.01); A61P 3/04 (2006.01); A61K 31/133 (2006.01); A61K 31/14 (2006.01); A61K 31/205 (2006.01); A61K 31/4164 (2006.01); A61K 31/5375 (2006.01); A61K 31/616 (2006.01); A61K 31/675 (2006.01); A61K 31/688 (2006.01); A61K 31/7036 (2006.01); A61K 31/7105 (2006.01); A61K 45/06 (2006.01); A61K 35/741 (2015.01)
CPC A61K 31/045 (2013.01) [A61K 31/133 (2013.01); A61K 31/14 (2013.01); A61K 31/205 (2013.01); A61K 31/4164 (2013.01); A61K 31/5375 (2013.01); A61K 31/616 (2013.01); A61K 31/675 (2013.01); A61K 31/688 (2013.01); A61K 31/7036 (2013.01); A61K 31/7105 (2013.01); A61K 35/741 (2013.01); A61P 3/04 (2018.01); A61K 45/06 (2013.01)] 20 Claims
 
1. A method of treating a disease or condition or causing weight loss comprising: treating a human subject, that has been identified as having elevated levels of trimethylamine (TMA), trimethylamine N-oxide (TMAO), or flavin monooxygenase 3 (FMO3) mRNA, with:
a) a first agent or first procedure that inhibits the TMA/FMO3/TMAO pathway to cause weight loss, and/or treat a first disease or first condition, or
b) a second agent or second procedure that is a non-antibiotic that inhibits said TMA/FMO3/TMAO pathway to treat a second disease or second condition,
wherein said first disease or first condition is selected from the group consisting of: obesity, dyslipidemia, arthritis pain, sleep apnea, diabetes-associated neuropathy, diabetes-associated cardiovascular disease, diabetes-associated cerebrovascular disease, diabetes-associated peripheral vascular disease, diabetes-associated retinopathy, diabetes-associated nephropathy, diabetes-associated ulceration, colorectal cancer, hepatocellular carcinoma, clear cell renal carcinoma, alcoholic steatohepatitis (ASH), alcoholic cirrhosis, Hepatitis C Virus driven (HCV-driven) liver fibrosis, Hepatitis B Virus driven (HBV-driven) liver fibrosis, primary sclerosing cholangitis (PSC), biliary atresia, gall stones, cholestasis, Cushing syndrome, impaired glucose tolerance, prediabetes, hyperglycemia, elevated insulin state, weight management, and arterial aneurysms,
wherein said second disease or second condition is selected from the group consisting of:
diabetes mellitus, insulin resistance, metabolic syndrome, nonalcoholic fatty liver disease (NAFD), and nonalcoholic steatohepatitis (NASH), and
wherein said first agent or procedure and/or said second agent or procedure is selected from the group consisting of:
i) 3,3-dimethyl-1-butanol (DMB) or a DMB derivative or related compound;
ii) acetylsalicylic acid with or without an enteric coating;
iii) an acetylsalicylic acid derivative with or without an enteric coating;
iv) a flavin monooxygenase 3 (FMO3) inhibitor;
v) a gut TMA lyase inhibitor;
vi) fecal microbiota transplantation;
vii) delivery of acetylsalicylic acid or derivative thereof directly to the colon or cecum of said subject;
viii) an antiplatelet agent;
ix) a TMA and/or TMAO sequestering agent;
x) a moiety from Table 1 selected from the group consisting of: i) a halomethyl choline, ii) a halomethyl betaine, iii) a halomethyl betaine salt, iv) a halomethyl betaine amide, and iv) a halomethyl dimethyl amine alcohol;
xi) a compound comprising at least one of: N,N-dimethylethanolamine (DMEA), N-methylethanolamine (MEA), ethanolamine (EA), trimethylsilyl ethanol, P-choline, and P,P,P-trimethyl ethanolphosphine; and
xii) an agent that inhibits trimethylamine-induced human trace amine-associated receptor 5 (TAAR5) activation.