Channel modulators

Patent metadata

Field	Value
Publication number	US-2016177298-A1
Application number	US-201514833041-A
Country	US
Kind code	A1
Filing date	Aug 21, 2015
Priority date	Aug 22, 2014
Publication date	Jun 23, 2016
Grant date	—

Abstract

The inventions relate to compositions and articles of manufacture comprising connexin modulators, pannexin modulators, gap junction modulators, hemichannel modulators, and pannexin channel modulators and their use, alone or in combination, in treating ocular and other disorders.

First claim

We claim:

1 . A method for treating a subject for glaucoma, DME, ocular fibrosis, retinal perfusion impairment, or ocular hypoxia, comprising administering a therapeutically effective amount of a gap junction modulator, a connexin modulator, a pannexin modulator, or a pannexin channel modulator to the eye of said subject.

2 . The method of claim 1 , where the glaucoma is characterized by glaucomatous ocular neuropathy and/or an intraocular pressure-associated neuropathy.

3 . The method of any one of claims 1 or 2 , wherein the connexin modulator is a connexin 43 modulator.

4 . The method of claim 3 , wherein the glaucoma is an intraocular pressure-associated neuropathy.

5 . The method of claim 4 , wherein the glaucoma is open-angle glaucoma or angle-closure glaucoma.

6 . The method of claim 5 , wherein loss of retinal ganglion cells is treated.

7 . The method of claim 1 , wherein inflammation in the inner retina is reduced.

8 . The method of claim 1 , wherein flow through the trabecular meshwork is increased.

9 . The method of claim 1 , wherein the gap junction modulator, connexin modulator, or pannexin modulator modulator is administered in combination with one or more of a Rho kinase inhibitor, prostaglandin, a prostaglandin analog, a carbonic anyhydrase inhibitor, an alpha 2 agonist, a beta blocker, F2α prostaglandin analogs, anti-apoptosis agents, N-methyl-D-aspartate (NMDA) receptor antagonists, and glutamate release inhibitors

10 . The method of claim 9 , wherein the gap junction modulator is a connexin modulator administered in combination with a Rho kinase inhibitor.

11 . The method of claim 1 , wherein treating ocular hypoxia reduces choroid inflammation.

12 . The method of claim 11 , wherein the connexin modulator is a connexin 43 modulator.

13 . The method of claim 11 , wherein the connexin modulator is a connexin 43 modulator and the connexin 43 modulator is adminstered in combination with an ocular treatment agent.

14 . The method of claim 11 , wherein choriocapillaris endothelial cell loss and/or choriocapillaris dropout is reduced.

15 . The method of claim 11 , wherein choroid inflammation is reduced.

16 . The method of claim 12 , wherein choriocapillaris endothelial cell loss is slowed or prevented.

17 . A method for treating a subject for retinal artery occlusion or central retinal vein occlusion, comprising administering a therapeutically effective amount of a connexin modulator or a pannexin modulator to the eye of said subject.

18 . The method according to any one of claims 1 , 3 , 11 or 17 , wherein the gap junction modulator, connexin modulator, or a pannexin modulator is selected from the group consisting of antisense oligonucleotides, antisense polynucleotides, compounds of Formula I, and compounds of formula VI.

19 . The method according to claim 18 , wherein at least one nucleotide of the oligonucleotide or polynucleotide is modified.

20 . The method according to claim 18 , wherein at least one nucleotide of the oligonucleotide or polynucleotide comprises at least one conformationally-strained nucleotide, at least one modified internucleoside linkage, at least one modified sugar moiety, and/or at least one modified nucleobase.

21 . The method according to claim 19 , wherein the conformationally-strained nucleotide is a locked nucleotide (LNA).

22 . The method according to claim 19 , wherein the conformationally-strained nucleotide is a bridged nucleic acid. (BNA).

23 . The method according to claim 21 , wherein the locked nucleotide is selected from one of the following types: 2′-O—CH 2 -4′ (oxy-LNA), 2′-CH 2 —CH 2 -4′ (methylene-LNA), 2′-NH—CH 2 -4′ (amino-LNA), 2′-N(CH 3 )—CH 2 -4′ (methylamino-LNA), 2′-S—CH 2 -4′ (thio-LNA), and 2′-Se—CH 2 -4′ (seleno-LNA).

24 . The method of claim 19 , wherein said antisense compound is an antisense oligonucleotide comprising naturally occurring nucleobases and an unmodified internucleoside linkage.

25 . The method of claim 18 , wherein said antisense compound is an antisense oligonucleotide comprising at least one modified internucleoside linkage.

26 . The method of claim 25 , wherein said modified internucleoside linkage is a phosphorothioate linkage.

27 . The method of claim 19 , wherein said antisense compound is an oligonucleotide comprising at least one modified sugar moiety or at least one modified nucleobase.

28 . The method of claim 18 , wherein said antisense compound comprises an oligonucleotide sequence selected from SEQ ID NO: 1-16, and the oligonucleotide is not more than 40 nucleotides in length.

29 . The method of claim 18 , wherein said antisense compound is targeted to at least about 8 nucleotides of a nucleic acid molecule encoding a connexin having a sequence selected from SEQ ID NO: 17.

30 . The method of any of claims 1 , 3 , 11 , or 18 - 29 , wherein said antisense compound is an antisense oligonucleotide between about 15 and about 35 nucleotides, or between about 15 and about 40 nucleotides in length.

31 . The method of claim 18 , wherein said antisense compound comprises a nucleobase sequence that is not more than 40 nucleotides in length selected from SEQ ID NO: 1-16 or a region of SEQ ID NO: 17.

32 . The method of any one of claims 1 , 3 , 11 , 13 , 17 , or 18 , wherein said connexin modulator is administered by topical, corneal, intraocular, intravitreal, subconjunctival, or periocular administration.

33 . The method of claim 32 , wherein the connexin modulator is administered by intraocular injection or by intravitreal injection.

34 . The method of any one of claims 32 or 33 , wherein the antisense compound is administered once.

35 . The method of any of the foregoing claims wherein the subject is a human.

36 . The method of claim 28 , wherein the antisense compound has at least about 80 percent, at least about 90 percent, at least about 95 percent, or at least about 97 percent homology to a polynucleotide having a sequence selected from SEQ ID NOs: 1 to 16 or a region of SEQ ID NO:17.

37 . The method according to claim 13 , wherein the ocular treatment agent is selected from anti-VEGF modulators, mTOR inhibitors, complement modulator, PDGF modulators such as PDGF antagonists, inhibitors of S1P production, squalamine, PEDF producers, tubulin binding agents, integrin inhibitors, and any mixture thereof.

38 . The method according to claim 37 , wherein the ocular treatment agent is selected from one or more of the following ocular treatment agents: alibercept, lampalizumab, sonepcizumab, fenretinide, ranibizumab, bivacizumab, protein ciliary neutrophic factor, a vascular endothelial growth factor-modulating compound, and a hypoxia-inducible factor 1-alpha-modulating compound, brimonidine, timolol, travoprost, dorzolamide, a carbonic anyhydrase inhibitor, a beta blocker, prostaglandain analogs, anti-apoptosis agents, N-methyl-D-aspartate (NMDA) receptor antagonists, or glutamate release inhibitors, a combination of an alpha 2 agonist and a beta blocker, a combination of an alpha 2 agonist and a carbonic anyhydrase inhibitor, and any mixture thereof.

39 . The method of claim

Assignees

• Auckland Uniservices Ltd
• Coda Therapeutics Inc

Inventors

• Green Colin Richard
• Kim Yeri
• Phillips Anthony
• Duft Bradford James

Classifications

• C12N15/1138

  against receptors or cell surface proteins · CPC title

• A61K9/0048

  Eye, e.g. artificial tears · CPC title

• A61K31/195

  having an amino group · CPC title

• A61K31/382

  having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) · CPC title

• A61P27/02

  Ophthalmic agents · CPC title