Methods of treating autophagy-associated disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits

Abstract

The invention provides methods of treating autophagy mediated diseases and disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits. In one embodiment, the invention provides a method of determining whether a subject suffers from, or is at risk of developing, and autophagy mediated disease state and/or condition by evaluating LC3 levels.

What is claimed is: 
     
         1 . A method of determining whether a patient or subject suffers from, or is at risk of developing an autophagy mediate disease state or condition, the method comprising determining LG3 levels on white blood cells or in plasma obtained from the subject and comparing the determined LC3 level to a control LC3 level, wherein an increase or decrease in LC3 levels compared to a control LC3 level indicates an increased likelihood that the subject suffers from or is at risk of developing an autophagy-mediated disease state or condition. 
     
     
         2 - 46 . (canceled) 
     
     
         47 . A pharmaceutical composition comprising:
 (a) an autophagy modulator (autostatin) in an effective amount; and optionally   (b) a pharmaceutically-acceptable carrier, additive and/or excipient, and further optionally   (c) at least one additional bioactive agent.   
     
     
         48 . The composition according to  claim 47  wherein said autophagy modulator is 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 and phenylmercuric acetate, pharmaceutically acceptable salts thereof and mixtures thereof. 
     
     
         49 . The composition according to  claim 47  wherein said autophagy modulator is 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 pharmaceutically acceptable salts thereof and mixtures thereof. 
     
     
         50 . The composition according to  claim 47  wherein said autophagy modulator is tetrachlorisophthalonitrile, phenylmercuric acetate, pharmaceutically acceptable salts thereof and mixtures thereof. 
     
     
         51 . The composition according to any of  claims 47 - 50  wherein said additional bioactive agent includes an additional autophagy modulator. 
     
     
         52 . The composition according to  claim 51  wherein said additional autophagy modulator is selected from the group consisting of 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, pharmaceutically acceptable salts thereof and mixtures thereof. 
     
     
         53 . The composition according to  claim 47  wherein said additional bioactive agent is an antibiotic or an antiviral agent. 
     
     
         54 . The composition according to  claim 53  wherein said antiviral agent is an anti-HIV agent, an anti-HBV agent, anti-influenza agent, an anti-herpes agent or an anti-HCV agent. 
     
     
         55 . The composition according to  claim 54  wherein said antiviral agent is an anti-HIV agent is a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor, a fusion inhibitor or a mixture thereof. 
     
     
         56 . The composition according to  claim 54  wherein said anti-HIV agent is 3TC (Lamivudine), AZT (Zidovudine), (−)-FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, among others, fuse on and mixtures thereof. 
     
     
         57 . The composition according to  claim 47  wherein said bioactive agent includes an anticancer agent. 
     
     
         58 . The composition according to  claim 57  wherein said anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and/or II, an alkylating agent, a microtubule inhibitor, a tyrosine kinase inhibitor, an EGF kinase inhibitor or an ABL kinase inhibitor. 
     
     
         59 . The composition according to  claim 57  wherein said anticancer agent is Aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with Polifeprosan 20 Implant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin; Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; Filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; gleevec (imatinib); goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; surafenib; talbuvidine (LDT); talc; tamoxifen; tarceva (erlotinib); temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate or a mixture thereof. 
     
     
         60 . (canceled) 
     
     
         61 . A method of treating an autophagy-mediated disease in a patient in need thereof comprising administering to said patient an effective amount of a composition according to  claim 47 . 
     
     
         62 . The method according to  claim 61  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. 
     
     
         63 . The method according to  claim 61  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. 
     
     
         64 . The method according to  claim 61  wherein said autophagy-mediated disease is selected from the group consisting of activator deficiency/GM2 gangliosidosis, alpha-mannosidosis, aspartylgluosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A 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. 
     
     
         65 . A method of treating cancer in a patient in need, comprising administering to said patient an effective amount of a composition according to  claim 57 . 
     
     
         66 . A method of treating an HIV infection or AIDS in a patient in need thereof, comprising administering to said patient an effective amount of a composition according to  claim 55  hereof. 
     
     
         67 - 71 . (canceled) 
     
     
         72 . A kit comprising:
 (a) at least one reagent which is selected from the group consisting of (i) reagents that detect a transcription product of the gene coding for a LC3 protein marker herein (ii) reagents that detect a translation product of the gene coding for LC3 protein marker, and/or reagents that detect a fragment or derivative or variant of said transcription or translation product;   (b) instructions for diagnosing, or prognosticating either an autophagy mediated disease state or condition or determining the propensity or predisposition of a subject to develop said autophagy mediated disease state or condition.   
     
     
         73 - 85 . (canceled)