METHOD FOR OPENING TIGHT JUNCTIONS

• US 20170166901A1
• Filed: 12/21/2016
• Published: 06/15/2017
• Est. Priority Date: 10/12/2007
• Status: Abandoned Application

• Current Assignee: The Provost Fellows and Scholars of the College of the Holy and Undivided Trinity of Queen Elizabeth, near Dublin
• Original Assignee: The Provost Fellows and Scholars of the College of the Holy and Undivided Trinity of Queen Elizabeth, near Dublin
• Inventors: Peter, Humphries, Kiang, Anna-Sophia, Campbell, Matthew
• Application Number:
  US15/387,617
• Publication Number:
  US 20170166901A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/0066 Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

The present invention is directed to a method and use of RNA interference (RNAi) for the transient, reversible and controlled opening of the tight junctions of the blood brain barrier and/or the blood retinal barrier. This method may be used in the treatment of many diseases and disorders which require the opening of the blood brain barrier and/or blood retinal barrier. Such methods generally involve the use of an RNAi-inducing agent, such as siRNA, miRNA, shRNA or an RNAi-inducing vector whose presence within a cell results in production of an siRNA or shRNA, targeting tight junction proteins to open the blood brain barrier and/or blood retinal barrier.

Claims

1-36. -36. (canceled)

37. A method for the treatment of a disease or disorder selected from a neurodegenerative disorder, a neuropsychiatric disorder, brain tumor, and retinal disorder, the method comprising the reversible, transient and controlled RNAi-mediated size selective opening of the paracellular pathway of the blood brain barrier wherein the method comprises:

identifying a subject at risk for developing the disease or disorder;

administering an effective amount of an RNAi inducing agent targeting tight junction proteins selected from occludin, claudin 1-19 or 21 by delivery of the RNAi inducing agent to result in the transient and reversible RNAi-mediated suppression of blood brain barrier tight junction protein transcripts in brain capillary endothelial or retinal endothelial cells and allow the permeation of active agents used in the treatment of the disease or disorder to the brain capillary endothelial and/or retinal cells; and

administering an active agent suitable for the treatment of the disease or disorder.

38. The method according to claim 37 wherein the RNAi agent is:

siRNA, shRNA or an RNAi-inducing vector whose presence within a cell results in production of an siRNA, shRNA or miRNA.

39. The method according to claim 37 involving systemic delivery of the RNAi inducing agent to the subject.

40. The method according to claim 37 wherein the RNAi inducing agent targeting the tight junction proteins transiently opens the blood brain barrier to allow delivery of the active agent across the blood brain barrier and the treatment comprises the simultaneous or sequential administration of the active agent and RNAi inducing agent.

41. The method according to claim 37 wherein a high concentration of the RNAi inducing agent is delivered to the subject.

42. The method according to claim 37 wherein systemic delivery takes place by hydrodynamic delivery or non-hydrodynamic delivery.

43. The method according to claim 37 wherein cationic polymers, modified cationic polymers, peptide molecular transporters, lipids, liposomes, non-cationic polymers and/or viral vectors are used for delivery of the RNAi inducing agent.

44. The method according to claim 37 wherein molecules less than approximately 1 kDa permeate across the brain capillary endothelial and/or retinal endothelial cells.

45. The method according to claim 37 wherein molecules less than approximately 800 Da, permeate across the brain capillary endothelial and/or retinal endothelial cells.

46. The method according to claim 37 wherein RNAi-mediated suppression commences from approximately 24 hours post delivery of the RNAi inducing agent and lasts up to approximately 72 hours post delivery of the RNAi inducing agent.

47. The method according to claim 37 wherein the RNAi inducing agent is siRNA.

48. The method according to claim 37 wherein the claudin is selected from claudin 1, claudin-5 and/or claudin-12.

49. The method according to claim 37 wherein the claudin is claudin-5.

50. The method according to claim 37 wherein the siRNA is selected from any one of SEQ ID Nos 1 and 2;

3 and 4;

5 and 6;

7 and 8;

9 and 10;

11 and 12;

13 and 14;

15 and 16;

17 and 18;

19 and 20;

21 and 22;

24 and 25;

26 and 27;

28 and 29;

or 30 and 31.

51. The method according to claim 37 wherein one or more siRNAs targeting different TJ proteins are used.

52. The method of claim 37 which allows the permeation of active agents less than 15 kDa.

53. The method of claim 37 involving viral mediated delivery of the RNAi inducing agent to the subject.