Antisense modulation of serum amyloid A4 expression

Details Antisense modulation of serum amyloid A4 expression Antisense modulation of serum amyloid A4 expression

2001-08-01

2002-09-24

LeGuyader, John L. (Department: 1635)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Method of regulating cell metabolism or physiology

C435S006120, C435S091100, C435S325000, C435S366000, C536S023100, C536S024310, C536S024330, C536S024500

Reexamination Certificate

active

06455308

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of serum amyloid A4. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding serum amyloid A4. Such compounds have been shown to modulate the expression of serum amyloid A4.
BACKGROUND OF THE INVENTION
Lipoproteins are globular, micelle-like particles that consist of a non-polar core of acylglycerols and cholesteryl esters, surrounded by an amphiphilic coating of protein, phospholipid and cholesterol. Lipoproteins have been classified into five broad categories on the basis of their functional and physical properties: chylomicrons (which transport dietary lipids from intestine to tissues); very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) and low density lipoproteins (LDL), (all of which transport triacylglycerols and cholesterol from the liver to tissues); and high density lipoproteins (HDL) (which transport endogenous cholesterol from tissues to the liver). All of these particles undergo continuous metabolic processing and have somewhat variable properties and compositions.
The protein components of lipoproteins are known as apolipoproteins and one family of apolipoproteins are the serum amyloid proteins, a family of homologous apolipoproteins which are associated with HDL and act as precursors of the amyloid A proteins found in amyloid fibril deposits formed during the process of amyloidosis. The serum amyloid proteins can be divided into two groups, the classical acute phase serum amyloid A proteins which are induced dramatically during an inflammatory acute phase response and the recently discovered constitutively expressed serum amyloid A4 protein (Sipe and Cohen,
J. Struct. Biol.,
2000, 130, 88-98; Uhlar and Whitehead,
Eur. J. Biochem.,
1999, 265, 501-523; Yamada,
Clin. Chem. Lab. Med.,
1999, 37, 381-388).
The properties and physiological significance of the serum amyloid A family of proteins in normal and disease states are poorly understood. Several functions have been proposed including depression of immune responses (Aldo-Benson and Benson,
J. Immunol.,
1982, 128, 2390-2392), inhibition of platelet aggregation (Zimlichman et al.,
J. Lab. Clin. Med.,
1990, 116, 180-186), and inhibition of cell adhesion to the extracellular matrix (Preciado-Patt et al.,
Eur. J. Biochem.,
1994, 223, 35-42). These observations suggest a role for serum amyloid A proteins in modulation of inflammation (Urieli-Shoval et al.,
J. Histochem. Cytochem.,
1998, 46, 1377-1384).
The serum amyloid A4 protein (also known as SAA4 and constitutive SAA; c-SAA), was cloned (Betts et al.,
Scand. J. Immunol.,
1991, 34, 471-482) and mapped to chromosome 11p15.1 (Sellar et al.,
Genomics,
1994, 19, 221-227). Serum amyloid A4 is an HDL apolipoprotein which comprises greater than 90% of the serum amyloid A proteins during homeostasis (de Beer et al.,
J. Lipid Res.,
1995, 36, 526-534). Originally found to be expressed in the liver, it has also been found to be expressed in epithelial components of a wide variety of normal tissues (Urieli-Shoval et al.,
J. Histochem. Cytochem.,
1998, 46, 1377-1384).
In chronic inflammatory diseases such as rheumatoid arthritis or familial Mediterranean fever, continuous elevation of serum amyloid A proteins is related to the development of amyloid A-type amyloidosis in which amyloid A fibrils derived from serum amyloid A proteins are deposited in vital organs and may compromise their function (Sipe,
Annu. Rev. Biochem.,
1992, 61, 947-975).
The potential role of serum amyloid A4 in the etiology of inflammation suggests that inhibition of its expression may prove to be a useful strategy with which to derive treatments for inflammatory disorders.
To date, inhibition of expression of serum amyloid A4 has not yet been examined as a means of treating inflammatory disorders. Currently, there are no known therapeutic agents that inhibit the synthesis of serum amyloid A4.
Consequently, there remains a long-felt need for agents capable of effectively inhibiting the expression of serum amyloid A4.
Antisense technology is emerging as an effective means of reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic and research applications involving modulation of serum amyloid A4 expression.
The present invention provides compositions and methods for modulating serum amyloid A4 expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding serum amyloid A4, and which modulate the expression of serum amyloid A4. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of serum amyloid A4 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 serum amyloid A4 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 serum amyloid A4, ultimately modulating the amount of serum amyloid A4 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding serum amyloid A4. As used herein, the terms “target nucleic acid” and “nucleic acid encoding serum amyloid A4” encompass DNA encoding serum amyloid A4, 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 serum amyloid A4. 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 serum amyloid A4. 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 encompassin

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