Oligonucleotide based therapeutics

• US 20060166920A1
• Filed: 12/27/2005
• Published: 07/27/2006
• Est. Priority Date: 12/27/2005
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Lippman, Marc E., Liu, Meilan, Xu, Liang
• Application Number:
  US11/318,799
• Publication Number:
  US 20060166920A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: H04L 47/10 Flow control; Congestion control
• CPC Class Codes: H04L 47/19 at layers above the network layer network arrangements for networked applications for scheduling or organising the servicing of application requests H04L67/60
• CPC Class Codes: H04L 47/2475 for supporting traffic characterised by the type of applications
• CPC Class Codes: H04L 47/30 in combination with information about buffer occupancy at either end or at transit nodes
• CPC Class Codes: H04L 47/32 by discarding or delaying data units, e.g. packets or frames
• CPC Class Codes: H04L 49/90 Buffering arrangements
• CPC Class Codes: H04L 49/9073 Early interruption upon arrival of a fraction of a packet
• CPC Class Codes: H04L 51/58 Message adaptation for wireless communication
• CPC Class Codes: H04L 67/04 specially adapted for terminals or networks with limited capabilities; specially adapted for terminal portability
• CPC Class Codes: H04L 67/60 Scheduling or organising the servicing of application requests, e.g. requests for application data transmissions using the analysis and optimisation of the required network resources admission control or resource allocation H04L47/70
• CPC Class Codes: H04L 69/12 Protocol engines
• CPC Class Codes: H04L 69/32 Architecture of open systems interconnection [OSI] 7-layer type protocol stacks, e.g. the interfaces between the data link level and the physical level
• CPC Class Codes: H04M 1/72403 with means for local support of applications that increase the functionality
• CPC Class Codes: H04M 1/72406 by software upgrading or downloading
• CPC Class Codes: H04M 1/72412 using two-way short-range wireless interfaces
• CPC Class Codes: H04M 1/7243 : with interactive means for internal management of messages
• CPC Class Codes: H04W 28/02 : Traffic management, e.g. flow control or congestion control
• CPC Class Codes: H04W 8/04 : Registration at HLR or HSS [Home Subscriber Server]

Abstract

The present invention relates to compositions comprising dsRNA. In particular, the present invention provides dsRNA comprising nucleotide sequence that is selectively complementary to bcl-xL mRNA sequence and that is not selectively complementary to bcl-xS mRNA sequence, recombinant nucleic acid comprising a vector and nucleic acid sequence for expressing bcl-xL dsRNA, pharmaceutical compositions comprising bcl-xL dsRNA, kits comprising such compositions, and methods of using the same in research, therapeutic, diagnostic and/or drug screening applications.

Claims

1. A composition comprising dsRNA, wherein said dsRNA comprises a sense RNA strand and an antisense RNA strand, wherein said sense and said antisense RNA strands form an RNA duplex, and wherein said duplex comprises a complementary nucleotide sequence that is selectively complementary to at least a part of bcl-xL mRNA sequence or equivalent sequences but not selectively complementary to bcl-xS mRNA sequence or equivalent sequences.

2. The composition of claim 1, wherein said complementary nucleotide sequence is substantially identical to a target sequence of about 19 to about 25 contiguous nucleotides in bcl-xL mRNA.

3. The composition of claim 1, wherein said sense RNA strand comprises one RNA molecule and said antisense RNA strand comprises one RNA molecule.

4. The composition of claim 1, wherein said RNA duplex comprises at least one linker between said sense and said antisense RNA strands.

5. The composition of claim 4, wherein said sense and said antisense RNA strands forming said RNA duplex are linked via a single-stranded hairpin.

6. The composition of claim 4, wherein said linker is a chemical linker.

7. The composition of claim 1, wherein said dsRNA comprises non-nucleotide material.

8. The composition of claim 1, wherein said sense and said antisense RNA strands are stabilized against nuclease degradation.

9. The composition of claim 1, wherein at least one of said RNA strands comprises a nucleotide overhang.

10. The composition of claim 9, wherein said overhang is a 3′

overhang.

11. A recombinant nucleic acid comprising a vector comprising nucleic acid sequence for expressing a dsRNA comprising a sense RNA strand and an antisense RNA strand, wherein said sense and said antisense RNA strands form an RNA duplex, and wherein said duplex comprises a complementary nucleotide sequence that is selectively complementary to at least a part of bcl-xL mRNA sequence or equivalent sequences but not selectively complementary to bcl-xS mRNA sequence or equivalent sequences.

12. The recombinant nucleic acid of claim 11, wherein said vector is selected from the group consisting of a plasmid, an adenoviral vector, an adeno-associated vector, a lentiviral vector, a retroviral vector, and a herpes virus vector.

13. The recombinant nucleic acid of claim 11, wherein said nucleic acid sequence for expressing a dsRNA comprises an inducible or regulatable promoter.

14. The recombinant nucleic acid of claim 11, wherein said vector comprises a human H1 or human U6 promoter.

15. The recombinant nucleic acid of claim 11, wherein said nucleic acid sequence for expressing a dsRNA comprises a sense RNA strand coding sequence in operable combination with i) a human U6 promoter and ii) a poly T termination sequence;

and an antisense RNA strand coding sequence in operable combination with i) a human U6 promoter and ii) a poly T termination sequence.

16. The recombinant nucleic acid of claim 11, wherein said recombinant nucleic acid is present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

17. A method of modifying levels of human bcl-xL mRNA, while concurrently unaffecting levels of bcl-xS mRNA, comprising administering to a host or host tissue an effective amount of a dsRNA comprising a sense RNA strand and an antisense RNA strand, wherein said sense and said antisense RNA strands form an RNA duplex, and wherein said duplex comprises a complementary nucleotide sequence that is selectively complementary to at least a part of bcl-xL mRNA sequence or equivalent sequences but not selectively complementary to bcl-xS mRNA sequence or equivalent sequences.

18. The method of claim 17, wherein said modifying reduces levels of bcl-xL mRNA.

19. The method of claim 17, wherein said host is a human being.

20. The method of claim 17, wherein said effective amount of said dsRNA is from about 1 nM to about 100 nM.