Syk-targeted nucleic acid interference

Abstract

The present invention provides methods and compositions for attenuating expression of Spleen Tyrosine Kinase, Syk. In general, the described methodology involves the use of RNAi constructs that are targeted to a Syk mRNA sequence.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of the filing date of U.S. Provisional Application No. 60 / 519,899, filed Nov. 14, 2003, entitled “Inhibition of phagocytosis with RNAi specific for cell surface receptors”, and of U.S. Provisional Application No. 60 / 564,459, filed Apr. 22, 2004, entitled “Short interfacing (si) RNA sequence(s) specific for the SH2 tyrosine kinase, Syk, inhibits phagocytosis by human macrophages”. The teachings of both of the above-mentioned applications are incorporated by reference herein in their entirety.BACKGROUND OF THE INVENTION [0002] Syk is an intracellular protein-tyrosine kinase that is widely expressed in hematopoietic cells, cells of the immune system and cells of epithelial lineages. Syk is involved in transducing signals from activated immunoglobulin receptors, such as Fcγ receptors and Fcε receptors. Syk is also implicated in the signaling triggered by receptors for G-CSF, IL-2, IL-3, IL-5, GM-CSF, IL-1...

AI Technical Summary

Benefits of technology

[0005] The disclosure provides, in part, RNAi constructs that target Syk and decrease Syk expression. Such constructs may be used in essentially any method where it is desirable to decrease the level of Syk protein. In particular, the disclosed nucleic acids will be useful in treating various disorders related to immune system function, such as immune thrombocytopenia and asthma.

[0006] In certain aspects, the disclosure provides RNAi constructs for inhibiting the expression of Syk. Such nucleic acids may comprise (a) an antisense polynucleotide strand that hybridizes to at least a portion of a Syk transcript and inhibits Syk expression; and (b) a sense polynucleotide that hybridizes to said antisense polynucleotide. The antisense and sense strands may be two separate nucleic acid strands, or the strands may be joined by a linker or by a stretch of further nucleic acid. For example, the RNAi construct may be a single stranded nucleic acid containing two regions that are complementary, thereby forming a hairpin nucleic acid with a stretch of double-stranded helix. Such hairpin nucleic acids are often processed into an siRNA inside a cell. Optionally, the portion of the nucleic acid that forms a double helix is about 19 to about 23 base pairs in length. The antisense polynucleotide strand may be complementary to a sequence of the human Syk mRNA of SEQ ID NO:1, or that of another animal of interest, such as mouse or rat. The antisense polynucleotide strand may be complementary to at least 5, 6, 7, 8, 10, 15, 20 or more nucleotides of a sequence selected from the group consisting of: SEQ ID Nos. 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14 and 15. The antisense polynucleotide may consist of a sequence that is complementary to a sequence selected from the group consisting of: SEQ ID Nos. 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14 and 15. The sense and antisense strands may be essentially any suitable nucleic acid, including RNA, DNA or other nucleic acid species that are not readily categorized as DNA or RNA. The sense and antisense strands need not be formed of the same nucleic acids. Either or both strands may include one or more modifications to the typical nucleic acid structure. For example, the antisense strand may comprise one or more of the following modifications: (a) a modification to the sugar-phosphate backbone; (b) a modification to a base portion of a nucleotide; and (c) a conjugated hydrophobic moiety. The sense strand may be similarly modified.

[0007] RNAi constructs may be formulated for administration to an organism. A pharmaceutical preparatio

Problems solved by technology

Also, decreased expression of Syk in monocytes using Syk antisense olignucleotides results in the decreased ability of these cells to ingest IgG-coated particles.

Images