DENGUE DIAGNOSIS AND TREATMENT

• US 20100068147A1
• Filed: 10/05/2007
• Published: 03/18/2010
• Est. Priority Date: 10/05/2006
• Status: Abandoned Application

• Current Assignee: Agency For Science Technology and Research, Novartis Ag
• Original Assignee: Agency For Science Technology and Research, Novartis Ag
• Inventors: Gu, Feng, Hibberd, Martin Lloyd, Vasudevan, Subhash, Fink, Joshua, Tolfvenstam, Thomas
• Application Number:
  US12/444,549
• Publication Number:
  US 20100068147A1
• Time in Patent Office: Days
• US Class Current: 424/9.200
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: G01N 2333/185 Flaviviruses or Group B arboviruses, e.g. yellow fever virus, japanese encephalitis, tick-borne encephalitis, dengue
• CPC Class Codes: G01N 2469/10 Detection of antigens from microorganism in sample from host
• CPC Class Codes: G01N 33/56983 Viruses
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

We describe a method of providing an indication useful in the diagnosis or prognosis of dengue, the method comprising detecting a change in the expression pattern or level of: (a) a ubiquitin-proteasome pathway protein; (b) a interferon-related protein; or (c) an NF-κB-mediated cytokine/chemokine response protein. We also describe a method of identifying a molecule suitable for the treatment or prevention of dengue, the method comprising determining if a candidate molecule is an agonist or antagonist of any one or more of these proteins.

Claims

1. A method of providing an indication useful in the diagnosis or prognosis of dengue, the method comprising detecting a change in the expression pattern or level of:

(a) a ubiquitin-proteasome pathway protein;

(b) a interferon-related protein;

or (c) an NF-κ

B-mediated cytokine/chemokine response protein.

15. A method according to claim 1, in which the ubiquitin-proteasome pathway protein is selected from the group consisting of:

a ubiquitin specific protease, a ubiquitin-conjugating enzyme, a ubiquitin ligase and a ubiquitin cleavage enzyme.

16. A method according to claim 15, in which the ubiquitin-proteasome pathway protein is selected from the group consisting of:

HERC1 (U50078), HERC2 (AF071172), HERC3 (D25215), HERC4 (NM_—

015601), C17orf27 (AB046774), DTX3L (AK025135), HERC6 (NM_—

017912), RNF36 (AL360161), ITCH (NM_—

031483), NEDD4 (NM_—

006154), UBB (NM_—

018955), UBE2L6 (NM_—

004223), UBE2I (NM_—

003345), Hdm2 (NM_—

002392), UBE1C (NM_—

003968), CBL (NM_—

005188), USP15 (AF106069), USP18 (NM_—

017414), PSMB9 (NM_—

002800), UBE2 (NM_—

003335), UBP43 (NM_—

017414), HERC5 (NM_—

016323), ATG7 (NM_—

006395), DUSP1 (NM_—

004417.2), DUSP18 (NM_—

152511.2), DUSP3 (NM_—

004090.2), DUSP5 (NM_—

004419.2), EIF3S5 (NM_—

003754), PPP1R15A (NM_—

014330.2), PSMB8 (NM_—

148919), UBE1L (NM_—

003335), UBE2L6 (NM_—

004223), UBE2S (NM_—

014501), UBE2W (NM_—

018299), USP24 (XM_—

165973.4) and WWP1 (NM_—

007013).

17. A method according to claim 15, in which the ubiquitin-proteasome pathway protein comprises ubiquitin specific protease 18 (USP18, GenBank Accession Number:

NM_—

017414) or Ubiquitin-conjugating enzyme E2L (UBE2L6, GenBank Accession Number;

NM_—

004223).

18. A method according to claim 15, in which the ubiquitin-proteasome pathway protein inhibitor comprises MG-132 (Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) or ALLN (N-Acetyl-Leu-Leu-Nle-CHO).

21. A method according to claim 1, in which the interferon-mediated protein is selected from the group consisting of:

IFNA1 (NM_—

024013), IFNB1 (NM_—

002176), IFNG (NM_—

000619), ATF3 (NM_—

004024) MKP-1 (NM_—

004417, AJ227912), IRF9 (NM_—

006084), STAT1 (AK022231, NM_—

007315), G1P2 (NM_—

005101), G1P3 (NM_—

002038), IF144 (NM_—

006417), IFIT1 (NM_—

001548), IFIT2 (AF026944), IFIT3 (AF026943), ISGF3G (NM_—

006084), IER3 (NM_—

003897), IFIT5 (NM_—

012420), IFRG28 (AJ251832), MDA5 (AF095844), SP110 (NM_—

004510), STAT1 (NM_—

007315), OAS1 (NM_—

016816), SOCS1 (NM_—

003745), ISG15 (NM_—

005101), IFIH1 (AL080107), OAS3 (NM_—

006187), IF144 (NM_—

006417), OAS2 (NM_—

002535), MxA (NM_—

002462), Viperin (AF026941, AF026942), OASL (AF063611), GBP1 (NM_—

002053), IRF1 (NM_—

002198), IRF7 (NM_—

004030), GBP2 (NM_—

004120), NMI (NM_—

004688), AIM2 (NM_—

004833), STAT2 (NM_—

005419), IF116 (NM_—

005531), SLAMF7 (NM_—

021181), GBP4 (NM_—

052941) and GBP5 (NM_—

052942).

22. A method according to claim 21, in which the interferon-mediated protein comprises viperin (GenBank Accession Number:

AF026941, AF026942) or interferon alpha (IFN-α

, GenBank Accession Number;

NM_—

024013).

26. A method according to claim 1, in which the polypeptide comprises an NF-κ

B-mediated cytokine/chemokine response protein.

27. A method according to claim 26, in which the NF-κ

B-mediated cytokine/chemokine response protein is selected from the group consisting of;

COX2 (NM_—

000963), INOS (NM_—

000625), IL10 (NM_—

000572), IL2 (NM_—

000586), IL6 (NM_—

000600), IL8 (M17017), RANTES (NM_—

002985), VEGF (NM_—

003376), NFKBIB (NM_—

002503), PAI1 (NM_—

000602), B2M (NM_—

004048), NFKBIA (NM_—

020529), TNFAIP3 (NM_—

006290), RIG-I (NM_—

014314), TNF (NM_—

000594), CCL4 (NM_—

002984), CCL5 (NM_—

002985), IL11b (NM_—

000881), IP-10 (NM_—

001565), I-TAC (NM_—

005409), CARD15 (NM_—

022162), CARD4 (NM_—

006092), CD14 (NM_—

000591), CD1A (NM_—

001763), CD2 (NM_—

001767), CD22 (NM_—

001771), CD276 (NM_—

025240), CD47 (NM_—

001777), CD59 (NM_—

000611), CD97 (NM_—

001784), CCL2 (NM_—

002982), CCR1 (NM_—

001295), CCR5 (NM_—

000579), CCR7 (NM_—

001838), CCRL2 (NM_—

003965), CXCL16 (NM_—

022059), IL1RN (NM_—

173842), IL10RB (NM_—

000628), IL13RA1 (NM_—

001560), IL16 (NM_—

004513), IL18 (NM_—

001562), IL18RAP (NM_—

003853), IL4R (NM_—

000418), IL8RA (NM_—

000634), IL8RB (NM_—

001557), PF4 (NM_—

002619), PBEF1 (NM_—

182790), TNFSF10 (NM_—

003810), TNFRSF1A (NM_—

001065), TNFRSF1B (NM_—

001066), TNFRSF25, (NM_—

148970), TNFRSF7 (NM_—

001242), TNFAIP2 (NM_—

006291) and TNFAIP8 (NM_—

014350).

28. A method according to claim 26, in which the NF-κ

B-mediated cytokine/chemokine response protein comprises IP-10 (GenBank Accession Number;

NM_—

001565).

29. A method according to claim 26, in which the NF-κ

B-mediated cytokine/chemokine response protein comprises I-TAC (GenBank Accession Number;

NM_—

005409).

2. A method of treatment or prevention of dengue in an individual, the method comprising modulating the level of expression of:

(a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein.

3. A method of identifying a molecule suitable for the treatment of dengue, the method comprising determining if a candidate molecule is an agonist or antagonist of (a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein.

4. A method according to Claim 3, in which the candidate molecule is exposed to (a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein in order to determine if the candidate molecule is an agonist or antagonist thereof

5. (canceled)

6. A method for providing an indication useful in the diagnosis or prognosis of dengue, the method comprising detecting a polymorphism in (a) a ubiquitin-proteasome pathway protein;

(b) a interferon-related protein;

or (c)an NF-κ

B-mediated cytokine/chemokine response protein, in a sample from the individual.

7. A method of identifying an agonist or antagonist of:

(a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein, the method comprising exposing the candidate molecule to a cell infected with dengue virus and determining an effect on viral function.

8. A method according to Claim 7, in which the viral function is selected from the group consisting of:

viral titre, viral infectivity, viral replication, viral packaging and viral transcription.

9. A method of identifying an agonist or antagonist of:

(a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein, the method comprising administering a candidate molecule to an animal suffering from dengue and determining whether the animal exhibits a decrease or increase in dengue virus replication.

10. (canceled)

11. A method of down-regulating a dengue viral function in a cell infected with dengue virus, the method comprising modulating the activity of (a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein in the cell.

12. A method according to Claim 11, in which the viral function is selected from the group consisting of:

viral titre, viral infectivity, viral replication, viral packaging and viral transcription.

13. (canceled)

14. (canceled)

19. (canceled)

20. (canceled)

23. A method of down-regulating a dengue viral function, for example viral titre, viral infectivity, viral replication, viral packaging or viral transcription, in a cell infected with dengue virus, the method comprising up-regulating the activity of viperin (GenBank Accession Number:

AF026941, AF026942) or interferon alpha (IFN-α

, GenBank Accession Number;

NM_—

024013) in the cell.

24. A method according to claim 23, further comprising up-regulating the activity of IFN-β

(GenBank Accession Number;

NM_—

002176) in the cell.

25. (canceled)

30. A method of providing an indication useful in the diagnosis or prognosis of dengue, the method comprising detecting a change in the expression pattern or level of any one or more of the following:

interferon alpha (IFN-α

, GenBank Accession Number;

NM_—

024013), IP-10 (GenBank Accession Number;

NM_—

001565) or I-TAC (GenBank Accession Number;

NM_—

005409).

31. A kit for diagnosis or prognosis of dengue, the kit comprising means for the detection of a change in the expression pattern or level of any one or more of the following:

(a) a ubiquitin-proteasome pathway protein;

(b) a interferon-related protein;

or (c) an NF-κ

B-mediated cytokine/chemokine response protein, together with instructions for use.

32. A kit for treatment or prevention of dengue in an individual, the kit comprising means for modulating the level of expression of:

(a) a ubiquitin-proteasome pathway protein;

or (b) a interferon-related protein, together with instructions for use.

33. A kit according to claim 32, comprising MG-132 (Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) or ALLN (N-Acetyl-Leu-Leu-Nle-CHO) or both.

34. A kit according to claim 32, further comprising any one or more of the following:

P4-PMO compounds 5′

SL and 3′

CS, any of the fullerenes described in U.S. Pat. No. 6,777,445 and Helioxanthin and/ or an analogue thereof (U.S. Pat. No. 6,306,899)

35-39. -39. (canceled)