COMPOUNDS THAT TARGET MYC microRNA RESPONSIVE ELEMENTS FOR THE TREATMENT OF MYC-ASSOCIATED CANCER

• US 20180195067A1
• Filed: 12/18/2017
• Published: 07/12/2018
• Est. Priority Date: 12/22/2016
• Status: Active Grant

• Current Assignee: BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Original Assignee: BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Inventors: Pandolfi, Pier Paolo, Bester, Assaf C., Tay, Yvonne
• Granted Patent: US 10,443,055 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2750/14143 viral genome or elements thereof as genetic vector

Abstract

Novel mIR-330 agents and their methods of use are provided. Methods of treating MYC-associated cancers are provided.

Claims

1. A method of treating a MYC-associated cancer in a subject in need thereof, the method comprising:

selecting a subject that overexpresses MYC; and

administering to the subject a pharmaceutical composition comprising a nucleic acid sequence having at least 80% complementarity to a micro RNA (miR) Responsive Element (MRE) sequence set forth as SEQ ID NO;

1, thereby treating cancer in the subject.

2. The method of claim 1, wherein the nucleic acid sequence has at least 90% complementarity, 95% complementarity, or 98% complementarity to the MRE sequence set forth as SEQ ID NO:

1.

5. The method of claim 1, wherein the nucleic acid sequence is further perfectly complementary to an MRE seed sequence set forth as SEQ ID NO:

2.

6. The method of claim 1, wherein the nucleic acid sequence comprises a miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound.

8. The method of claim 6, wherein the miRNA or siRNA is between 20 and 24 nucleotides in length.

9. The method of claim 1, wherein the MYC-associated cancer is further characterized by downregulation of hsa-miR-330-5p.

10. The method of claim 1, wherein the MRE is a MYC MRE.

11. The method of claim 1, wherein MYC expression is downregulated in the subject after administering the pharmaceutical composition to the subject.

12. The method of claim 1, wherein MYC mRNA cleavage is mediated or translation of MYC mRNA is inhibited.

13. The method of claim 1, wherein the MYC-associated cancer is liver cancer or colorectal cancer.

14. The method of claim 1, wherein the nucleic acid sequence is administered using a recombinant Adeno-Associated virus (AAV).

15. The method of claim 1, wherein the nucleic acid sequence is a double-stranded nucleic acid sequence having a sense strand and an antisense strand, wherein the antisense strand has at least 80% complementarity to the MRE sequence.

3. (canceled)

4. (canceled)

7. (canceled)

16. A method of targeting MYC overexpression in a cancer cell characterized by overexpression of MYC, comprising contacting the cell with a nucleic acid sequence having at least 80% complementarity to an MRE sequence set forth as SEQ ID NO:

1 to inhibit translation of the MYC mRNA.

17. The method of claim 16, wherein the nucleic acid sequence comprises a miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound.

18. (canceled)

19. An isolated nucleic acid comprising a sequence between 20 and 24 nucleotides in length having at least 80% complementarity to an MRE sequence set forth as SEQ ID NO:

1 and comprising a modified nucleotide.

20. The isolated nucleic acid sequence of claim 19, wherein the isolated nucleic acid sequence is further perfectly complementary to an MRE seed sequence set forth as SEQ ID NO:

2.

21. The isolated nucleic acid sequence of claim 20, having at least 90% complementarity, 95% complementarity, or 98% complementarity to the MRE sequence set forth as SEQ ID NO:

1.

24. The isolated nucleic acid sequence of claim 19, comprising an miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound.

22. (canceled)

23. (canceled)

25. (canceled)

26. A method of treating a MYC-associated cancer in a subject in need thereof, the method comprising:

selecting a subject that overexpresses MYC; and

administering to the subject a pharmaceutical composition comprising a modified miR-330 compound comprising SEQ ID NO;

3, thereby treating cancer in the subject.

27. A method of treating MYC-associated cancer in a subject in need thereof, the method comprising:

selecting a subject that overexpresses MYC; and

administering to the subject a pharmaceutical composition comprising a miR-330 analogue compound comprising SEQ ID N0;

3, thereby treating cancer in the subject.

28. An isolated nucleic acid comprising a sequence between 20 and 24 nucleotides in length comprising at least 90% identity to SEQ ID N0:

3, and comprising a modified nucleotide, wherein said nucleic acid sequence directs cleavage of MYC mRNA or inhibits translation of MYC mRNA.

29. The isolated nucleic acid sequence of claim 28, comprising at least 95% identity to SEQ ID NO:

3.

30. The isolated nucleic acid sequence of claim 28, comprising SEQ ID N0:

3.

31. A miR-330-5p analogue comprising a nucleic acid sequence comprising at least 90% identity to SEQ ID NO:

3, and having at least one modification selected from the group consisting of a deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, an amino-modified nucleotide, an alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate-modified nucleotide, a non-natural base-comprising nucleotide, an O-methyl modified nucleotide and a phosphorothioate.

32. The miR-330-5p analogue of claim 31, comprising at least 95% identity to SEQ ID NO:

3.

33. The miR-330-5p analogue of claim 31, wherein said miR-330-5p analogue inhibits translation of MYC mRNA.