Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Reexamination Certificate
2000-09-22
2003-01-07
McGarry, Sean (Department: 1635)
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
C435S006120, C435S091100, C435S375000, C435S458000, C536S023100, C536S024500, C536S025300
Reexamination Certificate
active
06503756
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Syntaxin 4 interacting protein. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Syntaxin 4 interacting protein. Such compounds have been shown to modulate the expression of Syntaxin 4 interacting protein.
BACKGROUND OF THE INVENTION
The proper regulation of glucose uptake in muscle and adipose tissue is critical in maintaining cellular energy homeostasis. Insulin, the primary hormonal regulator of this process, stimulates glucose transport by regulating the differential shuttling of GLUT4, a glucose transporter, recruiting it from a specialized intracellular compartment to the plasma membrane at the cell surface (Czech and corvera,
J. Diol. Chem
., 1999, 274, 1865-1868).
The SNARE (soluble NSF attachment protein receptors, where NSF stands for N-ethylmaleimide-sensitive fusion protein) hypothesis outlines the highly conserved process of recycling the GLUT4 transporter. This hypothesis states that the formation of specific complexes between membrane proteins on the transport vesicle (v-SNARE's) and membrane proteins located on the target membrane (t-SNARE's) drives vesicle transport. In support of this conclusion, several v- and t-SNARE's have been identified in muscle and adipose tissue and have been shown to interact with one another as postulated by the SNARE hypothesis. The v-SNAREs, VAMP2 and VAMP3/cellubrevin, have been shown to interact with the t-SNAREs, syntaxin 4 and SNAP-23. Once formed this complex then hinds to the cytosolic protein NSF through its interaction with alpha-SNAP, another soluble factor. Recently, studies have demonstrated that VAMP2/3, syntaxin 4, SNAP-23, and NSF are functionally involved in insulin-stimulated GLUT4 translocation in adipose cells and that this process might be affected in insulin resistant states such as type II diabetes (Cheatham et al., Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 15169-15173; Olson et al.,
Mol. Cell. Biol
., 1997, 17, 2425-2435; Volchuk et al.,
Mol. Biol. Cell
, 1996, 7, 1075-1082). Therefore, much effort has been placed in the direction of understanding these complexes and their role in glucose transport.
From further investigations another protein has been isolated that interacts with the t-SNARE syntaxin 4. This protein, syntaxin 4 interacting protein or synip has been shown to bind syntaxin 4, to be insulin-regulated, and to be involved in recruiting glucose transporters to the cell surface (Bennett,
Nat. Cell Biolog
., 1999, 1, E58-E60; Min et al.,
Mol. Cell
., 1999, 3, 751-760). The protein contains several binding motifs known to be involved in the organization of membrane signaling complexes and both the full length protein and the C-terminus interact selectively with syntaxin 4. Syntaxin 4 interacting protein expression is restricted to cells responsive to insulin, although the subcellular localization has not been determined. Disclosed in the PCT publication WO 99/54465 are the nucleotide and polypeptide sequences of synip and methods of detecting interactions between synip and syntaxin-4 (Min et al., 1999). The pharmacological modulation of syntaxin 4 interacting protein activity and/or expression may therefore be an appropriate point of therapeutic intervention in pathological conditions involving glucose transport.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of syntaxin 4 interacting protein. To date, investigative strategies aimed at modulating syntaxin 4 interacting protein function have involved the use of antibodies. Consequently, there remains a long felt need for agents capable of effectively inhibiting syntaxin 4 interacting protein function.
Antisense technology-is-emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of syntaxin 4 interacting protein expression.
The present invention provides compositions and methods for modulating syntaxin 4 interacting protein expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are. targeted to a nucleic acid encoding Syntaxin 4 interacting protein, and which modulate the expression of Syntaxin 4 interacting protein. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of Syntaxin 4 interacting protein in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of Syntaxin 4 interacting protein by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding Syntaxin 4 interacting protein, ultimately modulating the amount of Syntaxin 4 interacting protein produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Syntaxin 4 interacting protein. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Syntaxin 4 interacting protein” encompass DNA encoding Syntaxin 4 interacting protein, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of Syntaxin 4 interacting protein. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.
It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding Syntaxin 4 interacting protein. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is
Freier Susan M.
Wyatt Jacqueline
Isis Pharmaceuticals , Inc.
Licata & Tyrrell P.C.
McGarry Sean
Zara Jane
LandOfFree
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