Antisense modulation of RECQL2 expression

Details Antisense modulation of RECQL2 expression Antisense modulation of RECQL2 expression

2001-03-01

2002-06-04

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C435S455000, C435S006120, 51, C536S023100, C536S024100, C536S024500

Reexamination Certificate

active

06399378

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of RECQL2. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding RECQL2. Such compounds have been shown to modulate the expression of RECQL2.
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.
RECQL2 (also known as RECQL3, BLM, BLS and BS for Bloom's syndrome) was originally identified by a novel mapping method linking the gene product to the genetic disorder, Bloom's syndrome (Ellis et al.,
Cell
, 1995, 83, 655-666). The gene was identified by direct selection from a cDNA derived from a 250 kb segment of the genome to which RECQL2 had been assigned by somatic crossover point mapping. Since then, it has been confirmed that mutations in the RECQL2 gene are responsible for Bloom's syndrome. Bloom's syndrome is a rare recessive disorder associated with growth retardation, immunodeficiency and increased risk of malignancy at an early age (Ellis and German,
Hum. Mol. Genet
., 1996, 5, 1457-1463).
Disclosed in the U.S. Pat. No. 5,824,501 are the nucleic acid and protein sequences of the RECQL2 gene as are the sequences of mutated forms of the gene and vectors encoding said forms as well as cells that stably express said vectors (Ellis et al., 1998).
It has been demonstrated that the RECQL2 gene product colocalizes with some telomeric clusters suggesting a role in maintaining telomere length and/or structure (Yankiwski et al.,
Proc. Natl. Acad. Sci. U.S.A
., 2000, 97, 5214-5219).
Mouse embryos with a targeted mutation in the RECQL2 gene are developmentally delayed and die at embryonic day 13.5 (Chester et al.,
Genes Dev
., 1998, 12, 3382-3393.). Viable mice with targeted disruptions of the RECQL2 gene have been produced and, in those lacking exon 2, show a greater predispositon to cancers (Luo et al.,
Nat. Genet
., 2000, 26, 424-429).
While mutations and targeted disruptions resulting in altered protein expression in the RECQL2 gene are responsible for Bloom's syndrome, the normal function of the RECQL2 gene product and its regulation are still unclear. It is, however, believed to be involved in a DNA surveillance mechanism and is therefore a potential therapeutic target in conditions involving the production of aberrant DNA products, including the recognition of foreign DNA products as is the case upon viral infection.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of RECQL2. Consequently, there remains a long felt need for agents capable of effectively inhibiting and/or modulating RECQL2 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 RECQL2 expression.
The present invention provides compositions and methods for modulating RECQL2 expression
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding RECQL2, and which modulate the expression of RECQL2. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of RECQL2 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 RECQL2 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 RECQL2, ultimately modulating the amount of RECQL2 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding RECQL2. As used herein, the terms “target nucleic acid” and “nucleic acid encoding RECQL2” encompass DNA encoding RECQL2, 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 RECQL2. 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 RECQL2. The targeting process also includes determination of a site or sites within this gene for the ant

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