Methods for treating polycystic kidney disease (PKD) or other cyst forming diseases

• US 20080269123A1
• Filed: 10/02/2007
• Published: 10/30/2008
• Est. Priority Date: 04/03/2006
• Status: Active Grant

• Current Assignee: Stowers Institute for Medical Research
• Original Assignee: Stowers Institute for Medical Research
• Inventors: Li, Rong, Li, Xiaogang
• Granted Patent: US 8,007,790 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: C07K 14/4702 Regulators; Modulating activity
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

The present invention is directed to methods of treating or ameliorating an effect of a polycystic disease. More particularly, the methods include administering to a patient in need thereof an amount of a modulator of a tumor necrosis factor (TNF) pathway, which is sufficient to treat or ameliorate an effect of a polycystic disease. Methods of treating or ameliorating an effect of a polycystic kidney disease (PKD) are also provided. Methods are also provided for identifying a candidate compound that may be effective to treat or ameliorate an effect of a polycystic disease or to increase polycystin-2 (PC2) function or decrease Rab11-Family of Interacting Protein2 (FIP2) function. Further provided are methods for identifying a patient having, or who is at risk for developing, a polycystic disease or who would benefit from treatment with a TNF-alpha inhibitor.

Claims

1. A method of treating or ameliorating an effect of a polycystic disease comprising administering to a patient in need thereof an amount of a modulator of a tumor necrosis factor (TNF) pathway, which is sufficient to treat or ameliorate an effect of a polycystic disease.

2. The method according to claim 1, wherein the polycystic disease is selected from the group consisting of polycystic kidney disease (PKD), polycystic liver disease (PLD), polycystic ovary syndrome (PCOS), pancreatic cysts, and combinations thereof.

3. The method according to claim 2, wherein the polycystic disease is autosomal dominant polycystic disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).

4. The method according to claim 1, wherein the modulator of the TNF pathway is a TNF-alpha inhibitor.

5. The method according to claim 4, wherein the TNF-alpha inhibitor is selected from the group consisting of nucleic acids, polypeptides, polysaccharides, small organic or inorganic molecules, and combinations thereof.

6. The method according to claim 4, wherein the TNF-alpha inhibitor is selected from the group consisting of CytoFab (a polyclonal ovine anti TNF-alpha antibody Fab fragment), certolizumab pegol (a PEGylated Fab′

TM fragment of a humanized anti-TNF-alpha monoclonal antibody), IP-751 (a synthetic cannabinoid), adalimumab (a recombinant human IgG₁ monoclonal anti TNF-alpha antibody), etanercept (a dimeric fusion protein consisting of the extracellular ligand-binding domain of the human 75 kd (p75) TNF receptor linked to the Fc portion of human IgG₁), lenalidomide (a thalidomide analog, 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-dione), ITF-2357 (a hydroxamic acid linked to an aromatic ring), infliximab (a human-mouse chimeric IgG₁κ

anti-TNF-alpha monoclonal antibody), talactoferrin alfa (a recombinant human lactoferrin), pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone), simvastatin (butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α

,3α

,7β

,8β

(2S*,4S*),-8aβ

]]), onercept (a recombinant human soluble p55 TNF binding protein), tacrolimus ([3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20,21 (4H,23H)-tetrone, monohydrate), thalidomide (α

-(N-phthalimido)glutarimide), dersalazine (an azo derivative of a PAF antagonist and a 5-ASA with anti-TNFa activity), tgAAC94 (a recombinant adeno-associated virus serotype 2 (AAV2) vector genetically engineered to contain the cDNA for a human tumor necrosis factor receptor (TNFR)-immunoglobulin (IgG1) Fc fusion (TNFR;

Fc) gene), Genz-29155 (a small molecule TNF-alpha inhibitor), pomalidomide (4-amino-2-[(3RS)-2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione), VT-346 (a 43-kd secreted glycoprotein that is a human TNF-alpha inhibitor), UR-1505 (2-Hydroxy-4(-2,2,3,3,3-pentafluoropropoxy)-benzoic acid), PMI-001 (an extract from the roots of a perennial shrub), ENMD-1420 (a synthetic diaryl compound), golimumab (a fully human anti-TNF-alpha antibody), CYT-6091 (a nanotherapeutic in which TNF-alpha is covalently linked onto the surface of 30 nm particles of pegylated colloidal gold), Dom-0200 (an anti-TNF-alpha human domain antibody), ABX/0401 (a sc humanized anti-TNF-alpha monoclonal antibody), XPro-1595 (a dominant negative protein variant of TNF-alpha that selectively inhibits soluble TNF-alpha), anti-TNF-alpha, Borean (a C-type lectin domain (CTLD)-derived trimeric TNF-alpha antagonist), ABX/0402 (a humanized anti-TNF-alpha monoclonal antibody), TNF-alpha kinoid (a kinoid vaccine, which induces synthesis of polyclonal antibodies against TNF-alpha), CC-11006 (a class 11 thalidomide analog), apremilast ((+)-N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide), CC-11050 (an orally active selective cytokine inhibitory drug), YSIL6 (a small molecule inhibitor of TNF-alpha), tacrolimus, modified release (15,19-Epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy4,10,12,18-tetramethyl-8-(2-propenyl)-, (3S-(3R*(E(1S*,3S*,4S*)),4S*,5R*,8S*, 9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*))), NBE-P2 (anti-TNF-alpha protease), glyponectin (a highly active isoform of adiponectin), BN-006 (an orally active, short chain polypeptide down-regulator of TNF-alpha), LCP-Tacro (15,19-Epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21 (4H,23H)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-, (3S-(3R*(E(1S*,3S*,4S*)),4S*,5R*,8S*,9E, 12R*, 14R*, 15S*, 16R*, 18S*, 19S*,26aR*))), QR-440 (a naturally derived anti-inflammatory), CYT007-TNFQb (a vaccine designed to elicit anti-TNF-alpha antibodies), ESBA-105 (a fully humanized fragment of the VH/VL domains that inhibits TNF-alpha), CC-10015 (a thalidomide analog), Dom-0100 (an anti-TNFR1 human domain antibody), AN-0128 (3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)borane), PMI-005 (a plant-based TNF-alpha inhibitor), Y-40138 (1-Pyrimidylpiperazine), ARRY-438162 (a MEK inhibitor), MPL-104 (an anti-cytokine compound), TNF-alpha inhibitor, Devgen (an orally administered small molecule TNF-alpha inhibitor), IMD-1041 (an IKappa kinase-β

inhibitor), LT-ZMP001 (a tetrapeptide that blocks interaction of TNF with TNFR1), TPL2 inhibitors (small molecule inhibitors of tumor progression loci-2 such as 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile), thiothalidomide and hydroxythalidomide inhibitors of TNF-alpha (Phase 2 Discovery, Inc.), tacrolimus (delivered through a pulmonary drug delivery system) PMI-006c (an anti-inflammatory botanical extract), Pirfenidone (a bioavailable pyridine derivative), PN-0615 (an anti-TNF-alpha human monoclonal antibody), P-979 (Nicholas Piramal), Sphira (an orally active anti-TNF phytopharmaceutical), RPL-228 (a small-molecule synthetic mimetic of the cyclopentenone prostaglandins), THR-090717 (orally available TNF-alpha antagonist), PEG-sTNFR1, CDP-870, sLTr, CDP-571, MAK-195F, SelCIDs, forskolin, rTBP-1, D2E7, OR1384, tenidap, rapamycin, leflunomide, and combinations thereof.

7. The method according to claim 6, wherein the TNF-alpha inhibitor is etanercept.

8. The method according to claim 1, wherein the modulator regulates the activity of tissue necrosis factor (TNF)-alpha, TNF-alpha receptor, tissue necrosis factor receptor-1 (TNFR1), tissue necrosis factor receptor-2 (TNFR2), Fas-associated death domain protein (FADD), Rab11-Family of Interacting Protein2 (FIP2), TNF-receptor-associated death domain protein (TRADD), receptor-interacting protein-1 (RIP-1), TNF receptor-associated factors (TRAFs), phosphodiesterase IV (PDE4), p38 mitogen activated protein (MAP) kinase, fibrocystin, or a TNF-alpha-associated polypeptide.

9. The method according to claim 8, wherein the modulator is a p38 MAP kinase inhibitor, a PDE4 inhibitor, a TNFR1 inhibitor, or a TNFR2 inhibitor.

10. The method according to claim 9, wherein the p38 MAP kinase inhibitor is selected from the group consisting of semapimod (Decanediamide, N,N′

-bis[3,5-bis[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-, tetrahydrochloride), SCIO-469 (a small molecule p38-alpha kinase inhibitor), VX-702 (an orally-active p38 MAP kinase inhibitor), PS-540446 (a small molecule p38 kinase inhibitor), LP-7708 (orally active p38 MAP kinase inhibitor), CDP-146 (an orally-active small molecule p38 MAP kinase inhibitor), ARRY-797 (a 1,5-disubstituted-1H-indazole), GSK-681323 (an orally-active p38 MAP kinase inhibitor), R-1628 (Roche), p-38-alpha kinase inhibitors, Amph (an orally-active p38-alpha kinase inhibitor, Amphora), BMS-2 (Bristol-Myers Squibb), SD-282 (a p38-alpha MAP kinase inhibitor), p38 selective inhibitor (Kalypsys), LOC-7590 (an orally-active oncokinase inhibitor), p38 kinase inhibitors (a second generation allosteric p38 MAP kinase inhibitor, Kemia), KC-706 (an orally-active p38 MAP kinase inhibitor that binds to an allosteric (Phe-out) on p38 MAP kinase), TA-5493 (Tanabe Seiyaku), p38 MAPK siRNA (Merck), Org-223119 (Organon), Org-48775 (Organon), 856553 (GlaxoSmithKline), p38 signal inhibitor (Rexahn), p38 MAP Kinase inhibitor (a systemically-delivered p38 MAP kinase inhibitor, Chroma Therapeutics), CHR-3620 (a locally-delivered p38 MAP kinase inhibitor, Chroma Therapeutics), PH-797804 (Pfizer), p38 MAP kinase inhibitor (a benzimidazolone analog p38 MAP kinase inhibitor, Boehringer Ingelheim), Org-217993 (Organon), P38 MAP kinase inhibitor (a 7-amino-napthyridone-based analog, Merck), ARRY-614 (a p38/Tie-2 kinase inhibitor, Array BioPharma), p38-alpha kinase inhibitor (Xcovery), p38 kinase inhibitor (a pyrazolo-pyrimidine analog, Bristol-Myers Squibb), SD-169 (an indole-5-carboxamide p38-alpha MAP kinase-selective inhibitor), p38 MAP kinase inhibitor (a naphthyridinone analog p38 MAP kinase inhibitor, Merck), and combinations thereof.

11. The method according to claim 9, wherein the PDE4 inhibitor is selected from the group consisting of ibudilast (1-Propanone, 2-methyl-1-[2-(1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]), tetomilast (a non-peptidic, thiazole derivative, such as 2-Pyridinecarboxylic acid, 6-[2-(3,4-diethoxyphenyl)-4-thiazolyl]), cilomilast (an orally-active PDE4 inhibitor having the structure Cis-4-cyano4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid), roflumilast (Benzamide, 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)), IC486051 (a PDE4 inhibitor that targets PDE4A, PDE4B, PDE4C and PDE4D isoforms, Eli Lilly), IPL-455903 (an orally-active PDE4 inhibitor), MEM-1414 (Memory Pharmaceuticals), etazolate (an orally-available PDE4B inhibitor having the structure 1H-Pyrazolo[3,4-b]pyridine-5-carboxylic acid, 1-ethyl-4-[(1-methylethylidene)hydrazino]-, ethyl ester), MN-001 (an orally-active PDE4 inhibitor, Kyorin), PLX-369 (a selective PDE4B inhibitor), ND-1251 (an orally-active PDE4 inhibitor), ND-1510 (Evotec), apremilast ((CC-10004), an orally-active SelCID having the structure Acetamide, N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]), CC-11050 ((CC-5048), an orally active SelCID, Celgene), PDE IV inhibitor (a PDE4D inhibitor, deCODE), PDE IV inhibitors (Memory Pharmaceuticals), MEM-1917 (Memory Pharmaceuticals), oglemilast (an orally-active PDE4 inhibitor, Glenmark)), ELB-353 (an orally-active PDE4 inhibitor, Elbion), PDE IV inhibitor (Crystal Genomics), TPI-1100 (an inhaled RNAi or antisense oligonucleotide, Topigen), AVE-8112 (Sanofi-Aventis), CC-10015 (a thalidomide analog, Celgene), LAS-37779 (a topical PDE4 inhibitor, Almirall-Prodesfarma), CHF-5480 (a PDE4 inhibitor administered by inhalation, Chiesi), AV-411 (an orally-available formulation of ibudilast, Avigen), PDE IV inhibitor (Elbion), PDE IV inhibitor (Tanabe Seiyaku), 256066 (a PDE4 inhibitor administered by inhalation), PDE IV inhibitor (Aurigene Discovery Technologies), YM-393059 ((Å

±

)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate), AN-2728 (a topical PDE4 inhibitor), PDE IVB inhibitor (deCODE), GRC-4039 (Glenmark), DE-103 (Santen), RPL-554 (Verona Pharma), PDE IV Inhibitor (a PDE4 inhibitor administered by inhalation, Almirall-Prodesfarma), PDE IV inhibitor (VIA Pharmaceuticals), IPL-42 (Inflazyme), and combinations thereof.

12. The method according to claim 9, wherein the TNFR1 and TNFR2 inhibitors are selected from the group consisting of pirfenidone (2(1H)-Pyridinone, 5-methyl-1-phenyl-), GT-111 (an iv gene therapy containing a smart chimeric gene, Vascular Biogenics), CYT-6091 (aurimmune colloidal gold nanoparticle that is a PEGylated formulation of TNF-alpha), TNF-alpha kinoid (a kinoid vaccine which induces the synthesis of potent human polyclonal antibodies against TNF-alpha), apremilast (Acetamide, N-[2-[(1S)-1-(3-ethoxy4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]-), C-11050 (an orally-active SelCID (selective cytokine inhibitory drug) that inhibits TNF-alpha and phosphodiesterase IV), YSIL (a TNF-alpha antagonist), Dom-0100 (an anti-TNFR1 human domain antibody (dAb)), PMI-005 (a plant-based TNF-alpha inhibitor), BreMel/TNF-alpha (an unglycosylated, low molecular weight recombinant fusion protein consisting of a single chain antibody fragment (scFv) genetically fused to human TNF-alpha), Y-40138 (a TNF-alpha inhibitor), ARRY-438162 (Array BioPharma), LT-ZMP001 (a tetrapeptide that blocks the interaction of TNF with TNFR1), pirfenidone analog (InterMune), RPL-228 (a small-molecule synthetic mimetic of the cyclopentenone prostaglandins and topical TNF-alpha inhibitor), and combinations thereof.

13. The method according to claim 1, wherein the modulator acts upstream of TNF-alpha.

14. The method according to claim 1, wherein the modulator acts downstream of TNF-alpha.

15. The method according to claim 14, wherein the modulator is a Rab11-Family of Interacting Protein 2 (FIP2) inhibitor.

16. A method of treating or ameliorating an effect of a polycystic kidney disease (PKD) comprising administering to a patient in need thereof an amount of a TNF-alpha inhibitor that is sufficient to treat or ameliorate an effect of PKD.

17. The method according to claim 16, wherein the TNF-alpha inhibitor is etanercept.

18. A method for identifying a candidate compound that may be effective to treat or ameliorate an effect of a polycystic disease or to increase polycystin-2 (PC2) function or decrease Rab11-Family of Interacting Protein-2 (FIP2) function comprising:

(a) contacting a test cell that expresses PC-2 with an amount of a TNF-alpha pathway modulator, which is effective to modulate FIP2 expression in the test cell and/or to disrupt PC2 localization or function at a plasma membrane or a primary cilia of the test cell;

(b) further contacting the test cell from step (a) with a candidate compound; and

(c) determining whether the candidate compound (1) increases PC2 localization to the plasma membrane of the test cell, to the primary cilia of the test cell, or to both or (2) increases PC2 function or (3) decreases FIP2 expression in the test cell compared to a control cell treated in an identical fashion except that it was not contacted with the candidate compound, wherein a candidate compound that increases PC2 localization to the plasma membrane of the test cell, the primary cilia of the test cell, or both or increases PC2 function or decreases FIP2 expression in the test cell relative to the control cell is indicative that the candidate compound may be effective to treat or ameliorate the effects of a polycystic disease or to increase PC2 function or decrease FIP2 expression.

19. The method according to claim 18, wherein the polycystic disease is selected from the group consisting of polycystic kidney disease (PKD), polycystic liver disease (PLD), polycystic ovary syndrome (PCOS), pancreatic cysts, and combinations thereof.

20. The method according to claim 19, wherein the polycystic disease is autosomal dominant polycystic disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).

21. The method according to claim 18, wherein the candidate compound is selected from the group consisting of nucleic acids, polypeptides, polysaccharides, small organic or inorganic molecules, and combinations thereof.

22. The method according to claim 18, wherein the test cell is obtained from a normal or a PKD-affected organism.

23. The method according to claim 22, wherein the cell is a kidney cell from an inner medullary collecting duct (IMCD) cell line or an ADPKD2 cell line.

24. The method according to claim 18, which is a high throughput screen.

25. A method for identifying a patient who may benefit from treatment with a TNF-alpha inhibitor comprising determining whether a patient has an elevated level of TNF-alpha, FIP2, or both, compared to control levels of TNF-alpha, FIP2, or both in a patient population that does not have the polycystic disease, wherein a patient that has an elevated level of TNF-alpha, FIP2, or both compared to the control may benefit from treatment with a TNF-alpha inhibitor.