TREATMENT

• US 20130324471A1
• Filed: 08/17/2011
• Published: 12/05/2013
• Est. Priority Date: 08/17/2010
• Status: Active Grant

• Current Assignee: Yaqrit Limited
• Original Assignee: Yaqrit Limited
• Inventors: Jalan, Rajiv, Shah, Naina
• Granted Patent: US 9,889,176 B2
• Time in Patent Office: Days
• US Class Current: 514/15.4
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: G01N 2333/705 Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/28 Neurological disorders
• CPC Class Codes: G01N 2800/347 Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention derives from the finding that increased levels of Toll like receptor 4 (TLR4) is associated with liver failure and renal dysfunction and/or brain dysfunction and that by decreasing TLR4 levels in vivo, the kidney and brain consequences of liver disease that are precipitated by superimposed infection or inflammation may be reduced. Accordingly, the invention provides TLR4 antagonists for use in a method of treating an individual suffering from liver disease presenting with renal or brain dysfunction.

Claims

1. A method of treating an individual suffering from renal or brain dysfunction and liver disease, the method comprising administering to said individual an antagonist of Toll like receptor 4 (TLR4).

2. A method according to claim 1 wherein said individual is suffering from cirrhosis.

3. A method according to claim 1 wherein said individual is suffering from paracetamol overdose.

4. A method according to claim 1 wherein the individual is suffering from, or is at risk of one or more of the following, when compared to a subject not suffering from liver disease:

(a) renal dysfunction, and/or

(b) renal failure, and/or

(c) brain dysfunction, and/or

(d) brain swelling, and/or

(e) inflammation, injury or dysfunction in the kidney and/or brain,

5. A method according to claim 1, wherein the individual to be treated has an increased level of urinary TLR4 compared to the level of TLR4 in the urine of an individual not suffering from liver disease or renal dysfunction.

6. A method according to claim 1 wherein the antagonist is used for the treatment or prevention of renal dysfunction or renal failure;

or brain dysfunction or brain swelling.

7. A method according to claim 1 wherein said antagonist leads to:

(a) decreased expression of TLR4 in the kidney and/or brain of the individual; and

/or

(b) decreased levels of TLR4 in the kidney and/or brain of the individual; and

/or

(c) decreased activity of TLR4 in the kidney and/or brain of the individual; and

/or

(d) decreased levels of TLR4 in the urine of the individual.

10. A method of identifying a patient suitable for treatment of renal dysfunction and/or renal failure according to claim 1, the method comprising:

(a) measuring the level of TLR4 in the urine of the patient, and

(b) comparing the level of (a) with a known level of TLR4 from the urine of a control patient not suffering from liver disease or renal dysfunction,

wherein an increased level in (a) compared to the control indicates that the patient may be suitable for treatment of renal dysfunction and/or renal failure according to claim 1.

8. A method of treating or preventing renal dysfunction or renal failure or brain dysfunction or brain swelling in an individual in need thereof wherein the individual has liver disease or cirrhosis, said method comprising a step of administering to said individual an antagonist of Toll like receptor 4 (TLR4).

9. A method of diagnosing renal dysfunction or renal failure or of predicting renal failure in a patient having liver disease or cirrhosis, the method comprising:

(a) measuring the level of TLR4 in the urine of the patient, and

(b) comparing the level of (a) with a known level of TLR4 from the urine of a control patient not suffering from liver disease or renal dysfunction,

wherein an increased level in (a) compared to the control indicates that the patient has renal dysfunction or renal failure or that the patient is at increased risk of renal failure.

11. A method of identifying an agent suitable for use in treating or preventing renal dysfunction or brain dysfunction in cirrhosis, the method comprising determining whether a test agent is capable of decreasing the amount or activity of TLR4, wherein the ability to decrease the amount or activity of TLR4 indicates that the compound may be suitable for use in treating renal dysfunction or brain dysfunction in cirrhosis.

12. A method according to claim 11 wherein the amount or activity of TLR4 is assessed in the kidney and/or brain or in tissue or cells derived from the kidney and/or brain.

13. A method according to claim 11, comprising the step of administering a test agent to a bile duct ligated rat and determining whether the presence of the test agent leads to a decrease in the amount or activity of TLR4 in the kidney of the rat.