Antisense inhibitor of RECQL4 expression

Details Antisense inhibitor of RECQL4 expression Antisense inhibitor of RECQL4 expression

2001-02-23

2002-08-20

Wang, Andrew (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C435S325000, C435S091100, C435S091300, C536S024500

Reexamination Certificate

active

06436706

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of RECQL4. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding RECQL4. Such compounds have been shown to modulate the expression of RECQL4.
BACKGROUND OF THE INVENTION
Genomic integrity is critical to the health and survival of any organisms and cells have evolved multiple pathways for the repair of DNA damage.
One class of enzymes involved in the maintenance of genomic integrity and stability are DNA helicases. These proteins play important roles in DNA replication, repair, recombination and transcription by unwinding duplex genomic strands allowing the repair machinery access to damaged or mispaired DNA. For example, the RecQ family of helicases has been shown to be important players in linking cell cycle checkpoint responses to recombination repair (Chakraverty and Hickson,
BioEssays
, 1999, 21, 286-294; Frei and Gasser,
J. Cell Sci
., 2000, 113, 2641-2646; Wu et al.,
Curr. Biol
., 1999, 9, R518-520). More recently, these helicases have been implicated in the process of posttranscriptional gene silencing (PTGS) (Cogoni and Macino,
Science
, 1999, 286, 2342-2344). In this process, the helicase is required to separate the double-stranded DNA (dsDNA) before any hybridization and silencing mechanism could be initiated.
The RecQ family consists of five members and can be divided into two distinct groups according to whether they contain an additional carboxy- or amino-terminus group. One class containing the longest members of the family include genes known to be defective in several syndromes including the BLM gene in Bloom's syndrome, the WRN gene in Werner's syndrome and the RECQ4 gene in Rothmund-Thompson syndrome. Mutations in these genes lead to an increase in the incidence of cancer as well as other physiologic abnormalities (Karow et al.,
Curr. Opin. Genet. Dev
., 2000, 10, 32-38; Kawabe et al.,
Oncogene
, 2000, 19, 4764-4772).
The second class contains the RECQL gene and the RECQ5 gene which encode little more than the central helicase domain and have not been associated with any human disease.
RECQL4 (also known as RecQ protein-like 4, RTS for Rothmund Thomson Syndrome and RECQ4) was cloned by Kitao et al. along with the gene for RECQ5 (Kitao et al.,
Genomics
, 1998, 54, 443-452). A multi-tissue Northern analysis revealed that RECQL4 is predominantly expressed in the thymus and testis indicating a somewhat tissue-specific pattern of expression. The RECQL4 gene was mapped to chromosome 8q24, and chromosomal aberrations of several types have been associated with this site.
The protein and nucleic acid sequences of the human RECQL4 gene are disclosed in the European Patent Application EP0999273 and the corresponding PCT Publication WO 99/05284 (Shimamoto et al., 1999; Shimamoto et al., 2000). Also disclosed are antibodies to the RECQL4 protein, kits for diagnosing disease associated with RECQL4, transgenic and knockout animals of the RECQL4 gene and probes to the RECQL4 gene.
Kitao et al. reported that mutations in the RECQL4 gene are the cause of a subset of cases of Rothmund-Thomson syndrome, RTS (also known as poikiloderma congenitale) (Kitao et al.,
Nat. Genet
., 1999, 22, 82-84). RTS is a rare, autosomal recessive disorder characterized by abnormalities in the skin and skeleton, juvenile cataracts, premature aging and predisposition to cancers (Kitao et al.,
Genomics
, 1999, 61, 268-276; Lindor et al.,
Am. J. Med. Genet
., 2000, 90, 223-228). In these studies, Kitao found 3 patients with RTS who carried two types of mutations in the RECQL4 gene. These mutations were shown to be inherited from the parents in one family and not in ethnically matched controls, suggesting that mutations of RECQL4 are responsible for only a subset of RTS cases (Kitao et al.,
Nat. Genet
., 1999, 22, 82-84). Other types of mutations associated with the disorder include exon deletions, short string deletions, base pair changes resulting in premature termination and frameshifts.
While mutations in the RECQL4 gene are responsible for some cases of RTS, the normal function of the gene product and its regulation are still unclear. It is, however, believed to be involved in DNA metabolism, a potential therapeutic target in hyperproliferative conditions such as cancer.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of RECQL4. Consequently, there remains a long felt need for agents capable of effectively inhibiting and/or modulating RECQL4 activity.
Antisense technology is emerging as an effective means for selectively 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 RECQL4 expression.
The present invention provides compositions and methods for modulating RECQL4 expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding RECQL4, and which modulate the expression of RECQL4. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of RECQL4 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 RECQL4 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 RECQL4, ultimately modulating the amount of RECQL4 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding RECQL4. As used herein, the terms “target nucleic acid” and “nucleic acid encoding RECQL4” encompass DNA encoding RECQL4, 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 RECQL4. 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 mol

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