METHODS OF REDUCING A VIRAL INFECTION AND KITS THEREFORE

• US 20090104209A1
• Filed: 09/19/2008
• Published: 04/23/2009
• Est. Priority Date: 09/21/2007
• Status: Active Grant

• Current Assignee: Institut national de la recherche scientifique
• Original Assignee: Institut national de la recherche scientifique
• Inventors: LABONTE, PATRICK, SEIDAH, NABIL G.
• Granted Patent: US 8,088,571 B2
• Time in Patent Office: Days
• US Class Current: 424/172.100
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C12N 9/6408 Serine endopeptidases (3.4.21)
• CPC Class Codes: G01N 2333/96411 Serine endopeptidases (3.4.21)
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 33/569 for microorganisms, e.g. protozoa, bacteria, viruses

Abstract

A method for treating and/or preventing a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9)-susceptible viral infection comprising increasing a PCSK9 activity and/or expression in a biological system infected by the virus, whereby the increased PCSK9 activity and/or expression treats and/or prevents the viral infection in the biological system. Methods of classifying subjects, methods of screening and kits therefore.

Claims

1. A method for treating and/or preventing a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9)-susceptible viral infection comprising increasing a PCSK9 activity and/or expression in a biological system infected by the virus, whereby the increased PCSK9 activity and/or expression treats and/or prevents the viral infection in the biological system.

2. The method of claim 1, wherein the PCSK9-susceptible viral infection is caused by an enveloped virus.

3. The method of claim 1, wherein the enveloped virus is human immunodeficiency virus (HIV) or hepatitis C virus (HCV).

12. The method of claim 1, wherein the biological system is cells, a tissue, or an organ.

13. The method of claim 1, wherein the PCSK9 activity is increased by a PCSK9 polypeptide or a fragment thereof.

14. The method of claim 1, wherein the increasing of the PCSK9 activity and/or expression in the biological system comprises an increase of PCSK9 secretion.

15. The method of claim 1, wherein the biological system is a human subject.

4. A method of modulating the expression of a cellular receptor involved in viral infection at the surface of cells in a biological system, comprising modulating a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) activity and/or expression in the cells, whereby the modulating of PCSK9 activity and/or expression modulates the expression of the cellular receptor at the surface of the cells.

5. The method of claim 4, wherein the cellular receptor is a tetraspanin.

6. The method of claim 5, wherein the tetraspanin is CD81.

7. The method of claim 6, wherein the method is for decreasing the expression of CD81 at the surface of cells, and wherein the biological system is susceptible for viral infection by hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV), and comprises increasing a PCSK9 activity and/or expression in the cells, whereby the increasing of the PCSK9 activity and/or expression decreases the expression of the CD81 at the surface of the cells.

8. The method of claim 7, wherein the biological system susceptible for viral infection comprises hepatocytes or immune cells.

9. A method of identifying an agent for treating and/or preventing proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9)-susceptible viral infection comprising:

(a) selecting a test compound able to increase PCSK9 activity and/or expression; and

(b) assaying the ability of the compound to reduce (i) the PCSK9-susceptible viral infection in a biological system in vitro; and

/or (ii) CD81 expression at the surface of cells in the biological system in vitro,

wherein the ability of the compound to increase PCSK9 activity and/or expression, and to reduce (i) and/or (ii) is an indication that the test compound can treat and/or prevent the PCSK9-dependent viral infection.

10. A method of identifying a virus, the viral infection of which is treatable and/or preventable by a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) activity and/or expression, comprising:

(a) infecting a biological system that expresses PCSK9 with the virus,

wherein a lower level of infection in the biological system that expresses the PCSK9 than that in the biological system that does not express the PCSK9 is an indication that the viral infection is treatable and/or preventable by a PCSK9 activity and/or expression.

11. The method of claim 10, wherein the viral infection is a liver-specific viral infection.

16. A method of evaluating the susceptibility of a subject to a viral infection comprising (i) measuring the concentration of soluble proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) in a blood sample of the subject;

or (ii) determining whether the subject expresses a PCKS9 variant associated with a low or complete PCSK9 loss of function;

or (iii) a combination of (i) and (ii), wherein a lower amount of soluble PCSK9 in the blood sample of the subject than that in a control sample and/or a determination that the subject expresses the PCSK9 variant, is an indication that the subject is susceptible to a viral infection.

20. The method of claim 16, wherein the viral infection is a human immunodeficiency virus (HIV) infection or a hepatitis C virus (HCV) infection.

17. A method of classifying a subject having a viral infection comprising (i) measuring the concentration of soluble proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) in a blood sample of the subject;

or (ii) determining whether the subject expresses a PCKS9 variant associated with a low or complete PCSK9 loss of function;

or (iii) a combination of (i) and (ii), wherein the result of the measuring step and/or of the determining step enables the classification of the subject into a subgroup.

18. A method of selecting a treatment for a subject having a viral infection comprising (i) measuring the concentration of soluble proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) in a blood sample of the subject;

or (ii) determining whether the subject expresses a PCKS9 variant associated with a low or complete PCSK9 loss of function;

or (iii) a combination of (i) and (ii),

wherein a concentration of the soluble PCSK9 lower in the blood sample of the subject than that in a control blood sample and/or a determination that the subject expresses the PCSK9 variant, is an indication that a PCSK9 activator may be a useful treatment for the subject.

19. A method of evaluating the efficacy of a treatment against a viral infection in a treated subject, comprising measuring the concentration of soluble proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) in a blood sample of the subject, wherein a concentration of soluble PCSK9 higher in the blood sample of the subject than that in a control blood sample, is an indication that the treatment is efficient.

21. Kit comprising a proprotein convertase subtilisin/kexin type 9 preproprotein (PCSK9) activator, and at least one other therapeutic agent against a viral infection and/or instructions to use the activator for treating the viral infection.