Treatment of autophagy-related disorders

Patent metadata

Field	Value
Publication number	US-2016136123-A1
Application number	US-201414898062-A
Country	US
Kind code	A1
Filing date	May 29, 2014
Priority date	Jun 14, 2013
Publication date	May 19, 2016
Grant date	—

Abstract

The present invention relates to the use of neutral lipids, including triglycerides, diglycerides and monoglycerides which may be used to increase neutral lipids (lipid stores and/or lipid droplets) and neutral lipid stores in order to regulate (in particular, induce) autophagy and treat and/or prevent autophagy related disease states and/or conditions. In one embodiment, the invention relates to the use of neutral lipids and/or TRIM proteins which may be used to regulate (in particular, induce) autophagy, target autophagic substrates and treat and/or prevent autophagic disease states and/or conditions.

First claim

1 . A method of treating or reducing the likelihood of the onset of an autophagy-mediated disease in a patient in need thereof comprising administering to said patient an effective amount of a composition comprising an effective amount of an autophagy modulator selected from the group consisting of a neutral lipid, a TRIM protein or a mixtures thereof and optionally, another bioactive agent.

2 . The method according to claim 1 wherein said autophagy modulator is a neutral lipid.

3 . The method according to claim 1 wherein said autophagy modulator is a TRIM protein.

4 . The method according to claim 2 wherein said neutral lipid is effective in enhancing lipid stores and promoting lipid droplets in said patient such that enhancement of autophagy occurs.

5 . The method according to claim 2 wherein said neutral lipid is selected from the group consisting of neutral lipids selected from the group consisting of triglycerides, diglycerides, monoglycerides, glycolated mono- or diacylglycerdies, dolichol, polyprenol, polyprenal or very long chain fatty acids.

6 . The method according to claim 1 wherein said autophagy modulator is a TRIM protein selected from the group consisting of TRIM5α, TRIM1, TRIM6, TRIM10, TRIM17, TRIM22, TRIM41, TRIM55, TRIM72 and TRIM76, among others (including TRIM 1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM31, TRIM32, TRIM33, TRIM38, TRIM42, TRIM44, TRIM45, TRIM49, TRIM50, TRIM51, TRIM58, TRIM59, TRIM65, TRIM68, TRIM73, TRIM74 and TRIM76 and mixtures thereof.

7 . The method according to claim 4 wherein said TRIM protein is TRIM5α.

8 . The method according to claim 1 wherein said autophagy modulator is combined with another autophagy modulator selected from the group consisting of flubendazole, hexachlorophene, propidium iodide, bepridil, clomiphene citrate (Z,E), GBR 12909, propafenone, metixene, dipivefrin, fluvoxamine, dicyclomine, dimethisoquin, ticlopidine, memantine, bromhexine, norcyclobenzaprine, diperodon, nortriptyline, tetrachlorisophthalonitrile, phenylmercuric acetate, benzethonium, niclosamide, monensin, bromperidol, levobunolol, dehydroisoandosterone 3-acetate, sertraline, tamoxifen, reserpine, hexachlorophene, dipyridamole, harmaline, prazosin, lidoflazine, thiethylperazine, dextromethorphan, desipramine, mebendazole, canrenone, chlorprothixene, maprotiline, homochlorcyclizine, loperamide, nicardipine, dexfenfluramine, nilvadipine, dosulepin, biperiden, denatonium, etomidate, toremifene, tomoxetine, clorgyline, zotepine, beta-escin, tridihexethyl, ceftazidime, methoxy-6-harmalan, melengestrol, albendazole, rimantadine, chlorpromazine, pergolide, cloperastine, prednicarbate, haloperidol, clotrimazole, nitrofural, iopanoic acid, naftopidil, methimazole, trimeprazine, ethoxyquin, clocortolone, doxycycline, pirlindole mesylate, doxazosin, deptropine, nocodazole, scopolamine, oxybenzone, halcinonide, oxybutynin, miconazole, clomipramine, cyproheptadine, doxepin, dyclonine, salbutamol, flavoxate, amoxapine, fenofibrate, pimethixene, a pharmaceutically acceptable salt thereof and mixtures thereof.

9 . The method according to claim 1 wherein said autophagy-mediated disease is cancer, lysosomal storage diseases, Alzheimer's disease, Parkinson's disease; a chronic inflammatory disease, Crohn's disease, diabetes I, diabetes II, metabolic syndrome, an inflammation-associated metabolic disorder, liver disease, renal disease, cardiovascular disease, muscle degeneration and atrophy, symptoms of aging (including the amelioration or the delay in onset or severity or frequency of aging-related symptoms and chronic conditions including muscle atrophy, frailty, metabolic disorders, low grade inflammation, atherosclerosis and associated conditions such as cardiac and neurological both central and peripheral manifestations including stroke, age-associated dementia and sporadic form of Alzheimer's disease, pre-cancerous states, and psychiatric conditions including depression), spinal cord injury, infectious disease and developmental disease.

10 . The method according to claim 8 wherein said autophagy-mediated disease is selected from the group consisting of activator deficiency/GM2 gangliosidosis, alpha-mannosidosis, aspartylglucoaminuria, cholesteryl ester storage disease, chronic hexosaminidase deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, Gaucher Disease (Types I, II and III), GM! Ganliosidosis, including infantile, late infantile/juvenile and adult/chronic), Hunter syndrome (MPS II), I-Cell disease/Mucolipidosis II, Infantile Free Sialic Acid Storage Disease (ISSD), Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metachromatic Leukodystrophy, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Sanfilippo syndrome, Morquio Type A and B, Maroteaux-Lamy, Sly syndrome, mucolipidosis, multiple sulfate deficiency, Niemann-Pick disease, Neuronal ceroid lipofuscinoses, CLN6 disease, Jansky-Bielschowsky disease, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, Tay-Sachs or Wolman disease.

11 . The method according to claim 1 wherein said autophagy-mediated disease is selected from the group consisting of Type I and Type II diabetes, severe insulin resistance, hyperinsulinemia, hyperlipidemia, obesity, insulin-resistant diabetes, Mendenhall's Syndrome, Werner Syndrome, leprechaunism, lipoatrophic diabetes, acute and chronic renal insufficiency, end-stage chronic renal failure, glomerulonephritis, interstitial nephritis, pyelonephritis, glomerulosclerosis, GH-deficiency, GH resistance, Turner's syndrome, Laron's syndrome, short stature, increased fat mass-to-lean ratios, decreased CD 4 + T cell counts and decreased immune tolerance, chemotherapy-induced tissue damage, congestive heart failure, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Crohn's disease, peripheral neuropathy, muscular dystrophy, myotonic dystrophy, anorexia nervosa, a viral infection, and a bacterial infection.

12 . A pharmaceutical composition comprising an effective amount of a neutral lipid, a TRIM protein or a mixture of a neutral lipid and a TRIM protein, optionally in combination with an additional autophagy modulator, optionally further in combination with at least one additional bioactive agent, in combination with a pharmaceutically acceptable carrier, additive or excipient.

13 . The composition according to claim 12 wherein said neutral lipid is selected from the group consisting of neutral lipids selected from the group consisting of triglycerides, diglycerides, monoglycerides, glycolated mono- or diacylglycerdies, dolichol, polyprenol, polyprenal or very long chain fatty acids.

14 . The composition according to claim 12 wherein said TRIM protein is selected from the group consisting of TRIM5α, TRIM1, TRIM6, TRIM10, TRIM17, TRIM22, TRIM41, TRIM55, TRIM72 and TRIM76, among others (including TRIM 1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM31, TRIM 32, TRIM33, TRIM38, TRIM42, TRIM44, TRIM45, TRIM49, TRIM50, TRIM51, TRIM58, TRIM59, TRIM65, TRIM68, TRIM73, TRIM74 and TRIM76 and mixtures thereof

15 . The composition according to claim 12 wherein said additional autophagy modulator compound selected from the group consisting of flubendazole, hexachlorophene, propidium iodide, bepridil, clomiphene citrate (Z,E), GBR 12909, propafenone, metixene, dipivefrin, fluvoxamine, dicyclomine, dimethisoquin, ticlopidine, memantine, bromhexine, norcyclobenzaprine, diperodon, nortriptyline, tetrachlorisophthalonitrile, phenylmercuric acetate, benzethonium, niclosamide, monensin, bromperidol, levobunolol, dehydroisoandosterone 3-acetat

Assignees

• Deretic Vojo P
• Mandell Michale
• Stc Unm

Inventors

• Deretic Vojo P
• Mandell Michael

Classifications

• C12N9/93

  Ligases (6) · CPC title

• C12Q1/61

  involving triglycerides · CPC title

• G01N2500/20

  cell-free systems · CPC title

• G01N2333/92

  Triglyceride splitting, e.g. by means of lipase · CPC title

• G01N2405/00

  Assays, e.g. immunoassays or enzyme assays, involving lipids · CPC title