RNAi-MEDIATED INHIBITION OF H1F1A FOR TREATMENT OF OCULAR ANGIOGENESIS

• US 20100144844A1
• Filed: 02/16/2010
• Published: 06/10/2010
• Est. Priority Date: 12/29/2005
• Status: Active Grant

• Current Assignee: Arrowhead Pharmaceuticals, Inc.
• Original Assignee: Alcon Research Limited (Nestle SA)
• Inventors: Chatterton, Jon E., Bingaman, David P.
• Granted Patent: US 7,981,870 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/31 Combination therapy

Abstract

RNA interference is provided for inhibition of HIF1A mRNA expression for treating patients with ocular angiogenesis, particularly for treating retinal edema, diabetic retinopathy, sequela associated with retinal ischemia, posterior segment neovascularization (PSNV), and neovascular glaucoma, and for treating patients at risk of developing such conditions.

Claims

1. A method of attenuating expression of HIF1A mRNA in a subject, the method comprising:

administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising;

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of an mRNA corresponding to any one of SEQ ID NO;

3, SEQ ID NO;

9-SEQ ID NO;

48, and SEQ ID NO;

50-SEQ ID NO;

51,

wherein the expression of HIF1A mRNA is thereby attenuated.

2. The method of claim 1 wherein the interfering RNA comprises:

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of an mRNA corresponding to any one of SEQ ID NO;

3, and SEQ ID NO;

9-SEQ ID NO;

36.

3. The method of claim 1 wherein the interfering RNA comprises:

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of an mRNA corresponding to any one of SEQ ID NO;

37-SEQ ID NO;

48 and SEQ ID NO;

50-SEQ ID NO;

51.

4. The method of claim 1 wherein the interfering RNA comprises a region of at least 14 contiguous nucleotides having at least 85% sequence complementarity to, or at least 85% sequence identity with, the penultimate 14 nucleotides of the 3′

end of an mRNA corresponding to the sequence identified by the sequence identifier.

5. The method of claim 1 wherein the interfering RNA comprises a region of at least 15, 16, 17, or 18 contiguous nucleotides having at least 80% sequence complementarity to, or at least 80% sequence identity with, the penultimate 15, 16, 17, or 18 nucleotides, respectively, of the 3′

end of an mRNA corresponding to the sequence identified by the sequence identifier.

6. The method of claim 1 wherein the composition further comprises a second interfering RNA having a length of 19 to 49 nucleotides and comprising a region of at least 13 contiguous nucleotides having at least 90% complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of a second mRNA corresponding to any one of SEQ ID NO;

3, and SEQ ID NO;

9-SEQ ID NO;

51.

7. The method of claim 1 wherein the interfering RNA is an shRNA, siRNA, or miRNA.

8. The method of claim 1 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

9. The method of claim 1 wherein the composition is administered via in vivo expression from an interfering RNA expression vector.

10. A method of treating ocular angiogenesis in a subject in need thereof, the method comprising:

administering to an eye of the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising;

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of an mRNA corresponding to any one of SEQ ID NO;

3, SEQ ID NO;

9-SEQ ID NO;

48, and SEQ ID NO;

50-SEQ ID NO;

51,

wherein the ocular angiogenesis is treated thereby.

11. The method of claim 10 wherein the interfering RNA comprises:

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of an mRNA corresponding to any one of SEQ ID NO;

3, and SEQ ID NO;

9-SEQ ID NO;

36.

12. The method of claim 10 wherein the interfering RNA comprises:

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′

end of an mRNA corresponding to any one of SEQ ID NO;

37-SEQ ID NO;

48, and SEQ ID NO;

50-SEQ ID NO;

51.

13. The method of claim 10 wherein the subject has retinal edema, retinal ischemia or diabetic retinopathy.

14. The method of claim 10 wherein the interfering RNA is an shRNA, siRNA, or miRNA.

15. The method of claim 10 wherein the composition is administered via a topical, intravitreal, transcleral, conjunctival, subtenon, intracameral, subretinal, subconjunctival, or intracanalicular route.

18. The method of claim 10 wherein the composition is administered via in vivo expression from an interfering RNA expression vector.

19. A composition comprising interfering RNA having a length of 19 to 49 nucleotides and having a nucleotide sequence of any one of SEQ ID NO:

3, and SEQ ID NO;

9-SEQ ID NO;

51, or a complement thereof, and a pharmaceutically acceptable carrier.

20. The composition of claim 19 wherein the interfering RNA is an shRNA, siRNA, or miRNA.