Protection of cells from Alu-RNA-induced degeneration and inhibitors for protecting cells

Patent metadata

Field	Value
Publication number	US-9453226-B2
Application number	US-201414158357-A
Country	US
Kind code	B2
Filing date	Jan 17, 2014
Priority date	Jul 18, 2011
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

A method of protecting a cell includes inhibiting an inflammasome, MyD88, IL-18, VDAC1, VDAC2, caspase-8, and/or NFκB of the cell. Administering an inhibitor of MyD88, IL-18, VDAC1, VDAC2, caspase-8, and/or NFκB can protect the cell from Alu-RNA-induced degeneration. Protecting a cell, such as an retinal pigment epithelium (RPE), can be therapeutically useful in the context of age-related macular degeneration and geographic atrophy.

First claim

What is claimed is:

1. A method of protecting an retinal pigment epithelium (RPE) cell, a retinal photoreceptor cell, or a choroidal cell, comprising:
inhibiting one or more of an inflammasome of the cell; MyD88 of the cell; IL-18 of the cell; VDAC1 of the cell; VDAC2 of the cell; caspase-8 of the cell; and NFκB of the cell;
wherein the cell is protected against Alu-RNA-induced degeneration;
wherein inhibiting the inflammasome consists essentially of administering an inflammasome inhibitor selected from the group consisting of an NLRP3 inhibitor, a PYCARD inhibitor, an inflammosome inhibitor comprising a sequence selected from the sequences of SEQ ID NOS: 7-16, an inhibitor of Caspase-1, a peptide inhibitor of Caspase-1, a Caspase-1 inhibitor comprising the sequence of SEQ ID NO: 17, and the inflammosome inhibitors selected from: ion channel inhibitors; IkB-α inhibitors; antibodies selected from: Anti-ASC, Anti-NALP1, antibodies based on protein sequences selected from: ASC: ALR QTQ PYL VTD LEQ S; NALP1: MEE SQS KEE SNT EG-cys; Anti-NALP1, anti-IL-1β, anti-IL-18, anti-caspase-1, and anti-caspase-11; direct inhibitors of Caspase-1 and/or NLRP3; parthenolide; estrogen binding B-box proteins, COP, ICEBERG, and Z-WEHD-FMK; Caspase 1 and/or 4 inhibitors; Caspase-12 inhibitors; host-derived inhibitors of caspase-1; inhibitors of Nlrp1b inflammasome; virus expressed inhibitors of the inflammasome; potassium chloride; Cathepsin-B-inhibitors; Cytochalsin D; ROS inhibitors; ASC-1 inhibitors; NLRP3 inflammasome pan-caspase inhibitors; Microtubules; an isolated double-stranded RNA molecule that inhibits expression of NLRP3, and which can be conjugated to cholesterol or not, and at least one strand including the sequence: GUUUGACUAUCUGUUCUdTdT (SEQ ID NO: 7); an isolated double-stranded RNA molecule that inhibits expression of PYCARD, at least one strand of which includes the sequence of: 5′-GAAGCUCUUCAGUUUCAdTdT-3′ (SEQ ID NO: 12); and an isolated double-stranded RNA molecule that inhibits expression of PYCARD, at least one strand of which includes a sequence selected from: 5′-GAAGCUCUUCAGUUUCAdTdT-3′ (SEQ ID NO: 12); 5′-GGCUGCUGGAUGCUCUGUACGGGAA-3′ (SEQ ID NO: 13); and 5′-UUCCCGUACAGAGCAUCCAGCAGCC-3′ (SEQ ID NO: 14).

2. The method of claim 1 , wherein the inhibiting MyD88 comprises administering a MyD88 inhibitor.

3. The method of claim 2 , wherein the inhibitor is selected from the group consisting of a MyD88 inhibitor comprising a polypeptide sequence selected from the sequences of SEQ ID NO: 1, 54, 55, 60, and 61; and a MyD88 inhibitor comprising a double-stranded RNA molecule, at least one strand of which includes a sequence selected from SEQ ID NOS: 3, 4, 5, 6, and 56.

4. The method of claim 2 , wherein the My D88 inhibitor is selected from the group consisting of a MyD88 homodimerization inhibitor; Pepinh-MYD; a dominant negative or splice variant of MyD88; a MyD88 splice variants that lack exon 2; and MyD88 inhibitors as set forth in Table C.

5. The method of claim 4 , wherein the inhibitor is administered by intravitreous injection; subretinal injection; episcleral injection; sub-Tenon's injection; retrobulbar injection; peribulbar injection; topical eye drop application; release from a sustained release implant device that is sutured to or attached to or placed on the sclera, or injected into the vitreous humor, or injected into the anterior chamber, or implanted in the lens bag or capsule; oral administration; or intravenous administration.

6. A method of protecting an RPE cell, a retinal photoreceptor cell, or a choroidal cell, comprising:
inhibiting one or more of an inflammasome of the cell; MyD88 of the cell; IL-18 of the cell; VDAC1 of the cell; VDAC2 of the cell; caspase-8 of the cell; and NFκB of the cell;
wherein the cell is protected against Alu-RNA-induced degeneration;
wherein inhibiting the inflammasome comprises administering an inflammasome inhibitor selected from the group consisting of an NLRP3 inhibitor, a PYCARD inhibitor, an inflammosome inhibitor comprising a sequence selected from the sequences of SEQ ID NOS: 7-16, an inhibitor of Caspase-1, a peptide inhibitor of Caspase-1, a Caspase-1 inhibitor comprising the sequence of SEQ ID NO: 17, and the inflammosome inhibitors selected from: ion channel inhibitors; IkB-α inhibitors; antibodies selected from: Anti-ASC, Anti-NALP1, antibodies based on protein sequences selected from: ASC: ALR QTQ PYL VTD LEQ S; NALP1: MEE SQS KEE SNT EG-cys; Anti-NALP1, anti-IL-1β, anti-IL-18, anti-caspase-1, and anti-caspase-11; direct inhibitors of Caspase-1 and/or NLRP3; parthenolide; estrogen binding B-box proteins, COP, ICEBERG, and Z-WEHD-FMK; Caspase 1 and/or 4 inhibitors; Caspase-12 inhibitors; host-derived inhibitors of caspase-1; inhibitors of Nlrp1b inflammasome; virus expressed inhibitors of the inflammasome; potassium chloride; Cathepsin-B-inhibitors; Cytochalsin D; ROS inhibitors; ASC-1 inhibitors; NLRP3 inflammasome pan-caspase inhibitors; Microtubules; an isolated double-stranded RNA molecule that inhibits expression of NLRP3, and which can be conjugated to cholesterol or not, and at least one strand including the sequence: GUUUGACUAUCUGUUCUdTdT (SEQ ID NO: 7); an isolated double-stranded RNA molecule that inhibits expression of PYCARD, at least one strand of which includes the sequence of: 5′-GAAGCUCUUCAGUUUCAdTdT-3′ (SEQ ID NO: 12); and an isolated double-stranded RNA molecule that inhibits expression of PYCARD, at least one strand of which includes a sequence selected from: 5′-GAAGCUCUUCAGUUUCAdTdT-3′ (SEQ ID NO: 12); 5′-GGCUGCUGGAUGCUCUGUACGGGAA-3′ (SEQ ID NO: 13); and 5′-UUCCCGUACAGAGCAUCCAGCAGCC-3′ (SEQ ID NO: 14), wherein the inflammasome includes a protein encoded by PYCARD.

7. The method of claim 6 , wherein the inflammasome is selected from NLRP3 inflammasome, NLRP1 inflammasome, NLRC4 inflammasome, AIM2 inflammasome, and IFI16 inflammasome.

8. The method of claim 7 , wherein the inflammasome is the NLRP3 inflammasome.

9. The method of claim 1 , wherein the inflammasome inhibitor is selected from glybenclamide/glyburide; BAY11-7082 (CAS Number: 195462-67-7; also known as (E)-3-(4-Methylphenylsulfonyl)-2-propenenitrile); Anti-ASC and Anti-NALP1 and antibodies based on protein sequences selected from: ASC: ALR QTQ PYL VTD LEQ S; NALP1: MEE SQS KEE SNT EG-cys; Anti-NALP1, anti-IL-1β, anti-IL-18, anti-caspase-1, and anti-caspase-11; parthenolide; estrogen binding B-box proteins, COP, ICEBERG, and Z-WEHD-FMK; Ac-Tyr-Val-Ala-Asp-CHO (Ac-YVAD-CHO) or N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide (Ac-YVAD-CMK); Caspase-12 inhibitors; cellular PYRIN domain (PYD)-ony proteins (POP) family: cPOP1 and cPOP2; serpin proteinase inhibitor 9 (PI-9); BCL-2 and BCL-xL; auranofin; PYD homologs M13L-PYD, S013L, SPI-2 homologs CrmA, Serp2, SPI-2, NS1, Kaposi Sarcoma-associated Herpesvirus Orf63; potassium chloride; L-3-trans-(Propylcarbamoyl)oxirane-2-Carbonyl)-L-Isoleucyl-L-Proline Methyl Ester (“CA-074 Me”); Cytochalsin D; N-acetyl-L-cysteine (NAC), (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC); cellular pyrin domain (PYD) superfamily proteins, also known as M013; Z-VAD-FMK; colchicine; an isolated double-stranded RNA molecule that inhibits expression of NLRP3, and which can be conjugated to cholesterol or not, and at least one strand including the sequence: GUUUGACUAUCUGUUCUdTdT (SEQ ID NO: 7); an isolated double-stranded RNA molecule that inhibits expression of PYCARD, at least one strand of which includes the sequence of: 5′-GAAGCUCUUCAGUUUCAdTdT-3′ (SEQ ID NO: 12); and an isolated double-stranded RNA molecule that inhibits expression of PYCARD, at least one strand of which includes a sequence selected from: 5′-GAAGCUCUUCAGUUUCAdTdT-3′ (SEQ ID NO: 12); 5′

Assignees

• Univ Kentucky Res Found

Inventors

• Ambati Jayakrishna
• Tarallo Valeria

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• G01N33/6869

  Interleukin · CPC title

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title