Micro-RNAs and micro-RNA inhibitors to modulate blood vessel growth, patterning, tumor growth and malignant disease and method for making and using them

Patent metadata

Field	Value
Publication number	US-9242000-B2
Application number	US-201314057235-A
Country	US
Kind code	B2
Filing date	Oct 18, 2013
Priority date	Oct 18, 2012
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

In alternative embodiments, the invention provides compositions and methods comprising use of microRNAs and microRNA inhibitors to modulate blood vessel growth (angiogenesis), e.g., act as anti-angiogenic agents, and modulate cell and tumor microenvironment patterning, cancer cell and tumor growth and malignant disease (metastasis). In alternative embodiments, the invention provides compositions and methods that can sensitize blood vessels, e.g., tumor blood vessels, to radiation and agents and chemotherapies that cause DNA damage.

First claim

What is claimed is:

1. A method for inhibiting DNA repair enzymes TREX1 and TREX2, or destabilizing a DNA repair response of a cell, or forcing or stimulating a cell to undergo cell cycle arrest or cell death, comprising:
(a) providing a composition comprising a microRNA-103 (miRNA-103, or miR103) or equivalents thereof, or chemically modified and stabilized forms of miR-103, and/or a FANCF gene expression-inhibiting composition or a FANCF gene expression-inhibiting microRNA or siRNA; and
(b) administering a sufficient amount of the composition, microRNA-103 or equivalents, and/or a FANCF gene expression-inhibiting composition or a FANCF gene expression-inhibiting microRNA or siRNA, to inhibit DNA repair enzymes TREX1 and TREX2, or destabilize a DNA repair response of a cell, or force or stimulate a cell to undergo cell cycle arrest or cell death.

2. The method of claim 1 , wherein the composition comprises a pharmaceutical composition administered in vivo.

3. The method of claim 1 , wherein the composition is administered intravenously (IV), or by vessel-targeted nanoparticle or liposome delivery.

4. The method of claim 1 , wherein the composition administered to inhibit DNA repair enzymes TREX1 and TREX2, or destabilize a DNA repair response of a cell, or force or stimulate a cell to undergo cell cycle arrest or cell death comprises a microRNA-103 (miRNA-103, or miR103).

5. The method of claim 2 , wherein the pharmaceutical composition is formulated for administration parenterally, topically, orally, by local administration, by aerosol or transdermally.

6. The method of claim 2 , wherein the pharmaceutical composition is formulated for administration as a lipid, a nanoparticle, a tablet, a capsule or a spray.

7. The method of claim 2 , wherein the microRNA-103, the chemically modified or stabilized forms of miR-103, the FANCF gene expression-inhibiting composition or the FANCF gene expression-inhibiting microRNA or siRNA are formulated as a lyophilized microRNA or a lyophilized composition.

8. The method of claim 7 , wherein the lyophilized microRNA or lyophilized composition are reconstituted with a diluent.

9. The method of claim 8 , wherein the diluent comprises a sterile water or a sterile saline for injection.

10. The method of claim 8 , wherein the reconstituted microRNA or composition are administered as a subcutaneous injection or as an intravenous infusion.

11. The method of claim 1 , wherein the composition administered to inhibit DNA repair enzymes TREX1 and TREX2, or destabilize a DNA repair response of a cell, or force or stimulate a cell to undergo cell cycle arrest or cell death comprises a FANCF gene expression-inhibiting composition.

12. The method of claim 1 , wherein the composition administered to inhibit DNA repair enzymes TREX1 and TREX2, or destabilize a DNA repair response of a cell, or force or stimulate a cell to undergo cell cycle arrest or cell death comprises a FANCF gene expression-inhibiting microRNA or siRNA.

13. The method of claim 1 , wherein the composition administered to inhibit DNA repair enzymes TREX1 and TREX2, or destabilize a DNA repair response of a cell, or force or stimulate a cell to undergo cell cycle arrest or cell death comprises a chemically modified and stabilized forms of miR-103.

14. The method of claim 1 , wherein the microRNA comprise one or more 5′-end modifications, or a guide strand modification.

15. The method of claim 14 , wherein the 5′-stem modification comprises a 2′-modified ribose sugar or a 2′-modified nucleotide.

16. The method of claim 14 , wherein the 2′-modified nucleotide comprises a 2′-O-methyl modified nucleotide or a 2′-O-allyl nucleotide.

17. The method of claim 1 , wherein the microRNA or siRNA comprise a phosphorothioate linkage or a 2′-O-methyl modification.

18. The method of claim 1 , wherein the microRNA or siRNA comprise a sugar-modified nucleoside or a bicyclic sugar moiety.

19. The method of claim 18 , wherein the bicyclic sugar moiety comprises a 2 linked biradical group, or the bicyclic sugar moiety is bridged between the 2′ and 4′ carbon atoms with a biradical group selected from —O—(CH2)x-, —O—CH2-, —O—CH2CH2-, —O—CH(alkyl)-, —NH—(CH2)P—, —N(alkyl)-(CH2)x-, —O—CH(alkyl)-, —(CH(alkyl))-(CH2)x-, —NH—O—(CH2)x-, —N(alkyl)-O—(CH2)x-, or —O—N(alkyl)-(CH2)x-, wherein x is 1, 2, 3, 4 or 5.

20. The method of claim 18 , wherein the sugar-modified nucleoside comprises a 4′-thio modified nucleoside.

Assignees

• Univ California

Inventors

• Cheresh David
• Anand Sudarshan
• Advani Sunil

Classifications

• C12N2310/113

  targeting other non-coding nucleic acids, e.g. antagomirs · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title