Treating renal and liver dysfunction with TLR4 antagonists

• US 9,889,176 B2
• Filed: 08/17/2011
• Issued: 02/13/2018
• Est. Priority Date: 08/17/2010
• Status: Active Grant

• Current Assignee: Yaqrit Limited
• Original Assignee: Yaqrit Limited
• Inventors: Jalan, Rajiv, Shah, Naina
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US13/817,374
• Publication Number:
  US 20130324471A1
• Time in Patent Office: 2,372 Days
• Field of Search: None
• 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 a human individual suffering from alcoholic acute on chronic liver failure (ACLF) that leads to renal tubular injury that releases TLR4 into the urine, wherein said ACLF is at least partially precipitated by alcoholic hepatitis and is associated with superimposed infection and/or inflammation of the kidney, the method comprising administering an antagonist of Toll like receptor 4 (TLR4) to the individual.

2. A method according to claim 1 wherein said ACLF is further associated with a paracetamol overdose.

3. A method according to claim 1, wherein the ACLF is associated with, or places the treated individual at increased risk of developing, one or more of the following conditions when compared to a normal individual:

(a) renal dysfunction,

(b) renal failure,

(c) kidney inflammation or dysfunction.

4. The method of claim 1, further wherein, the treated individual prior to treatment is diagnosed as suffering from said ACLF, and based thereon being suitable for said treatment, by a diagnostic method comprising the following:

(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 cirrhosis and renal dysfunction;

wherein an increased level in (a) compared to the control (b) indicates that the patient comprises said ACLF and is suitable for said treatment method.

5. The method of claim 1, wherein the ACLF is characterized by abnormally elevated TLR4 in the patient'"'"'s urine compared to the level of TLR4 in the urine of an individual not suffering from ACLF.

6. The method of claim 1, wherein the patient with alcoholic hepatitis and associated ACLF, prior to treatment, has been determined to have an increased level of TLR4 in the urine of the patient compared to a control level of TLR4 of a patient not suffering from alcoholic hepatitis and associated ACLF.