| Antisense iap oligonucleotides and uses thereof -> Monitor Keywords |
|
|
 
Antisense iap oligonucleotides and uses thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.)Antisense iap oligonucleotides and uses thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070123481, Antisense iap oligonucleotides and uses thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 09/672,717 (now allowed), filed Sep. 28, 2000. FIELD OF THE INVENTION [0002] The invention relates to antisense IAP oligonucleotides and methods of using them to increase apoptosis. BACKGROUND OF THE INVENTION [0003] One way by which cells die is referred to as apoptosis, or programmed cell death. Apoptosis often occurs as a normal part of the development and maintenance of healthy tissues. The process may occur so rapidly that it is difficult to detect. [0004] The apoptosis pathway is now known to play a critical role in embryonic development, viral pathogenesis, cancer, autoimmune disorders, and neurodegenerative diseases, as well as other events. The failure of an apoptotic response has been implicated in the development of cancer, autoimmune disorders, such as lupus erythematosis and multiple sclerosis, and in viral infections, including those associated with herpes virus, poxvirus, and adenovirus. [0005] Baculoviruses encode proteins that are termed inhibitors of apoptosis (IAPs) because they inhibit the apoptosis that would otherwise occur when insect cells are infected by the virus. These proteins are thought to work in a manner that is independent of other viral proteins. The baculovirus IAP genes include sequences encoding a ring zinc finger-like motif (RZF), which is presumed to be directly involved in DNA binding, and two N-terminal domains that consist of a 70 amino acid repeat motif termed a BIR domain (Baculovirus IAP Repeat). [0006] The role of apoptosis in cancer has only recently been appreciated. The identification of growth promoting "oncogenes" in the late 1970's gave rise to an almost universal focus on cellular proliferation that dominated research in cancer biology for many years. Long-standing dogma held that anti-cancer therapies preferentially targeted rapidly dividing cancer cells relative to "normal" cells. This explanation was not entirely satisfactory, since some slow growing tumors are easily treated, while many rapidly dividing tumor types are extremely resistant to anti-cancer therapies. Progress in the cancer field has now led to a new paradigm in cancer biology wherein neoplasia is viewed as a failure to execute normal pathways of programmed cell death. Normal cells receive continuous feedback from their neighbors through various growth factors, and commit "suicide" if removed from this context. Cancer cells somehow ignore these commands and continue inappropriate proliferation. Cancer therapies, including radiation and many chemotherapies, have traditionally been viewed as causing overwhelming cellular injury. New evidence suggests that cancer therapies actually work by triggering apoptosis. [0007] Both normal cell types and cancer cell types display a wide range of susceptibility to apoptotic triggers, although the determinants of this resistance are only now under investigation. Many normal cell types undergo temporary growth arrest in response to a sub-lethal dose of radiation or cytotoxic chemical, while cancer cells in the vicinity undergo apoptosis. This provides the crucial treatment "window" of appropriate toxicity that allows successful anti-cancer therapy. It is therefore not surprising that resistance of tumor cells to apoptosis is emerging as a major category of cancer treatment failure. [0008] Compared to the numerous growth-promoting oncogenes identified to date (>100), relatively few genes have been isolated that regulate apoptosis. The Bcl-2 gene was first identified as an oncogene associated with the development of follicular lymphomas. In contrast to all other oncogenes identified to date, Bcl-2 displays no ability to promote cell proliferation, and-instead has been demonstrated to suppress apoptosis by a variety of triggers. Elevated Bcl-2 expression is associated with a poor prognosis in neuroblastoma, prostate and colon cancer, and can result in a multidrug resistant phenotype in vitro. Although the study of Bcl-2 has helped revolutionize cancer paradigms, the vast majority of human malignancies do not demonstrate aberrant Bcl-2 expression. [0009] In contrast to the findings with Bcl-2, mutation of the p53 tumor suppresser gene has been estimated to occur in up to 50% of human cancers and is the most frequent genetic change associated with cancer to date. The p53 protein plays a crucial role in surveying the genome for DNA damage. The cell type and degree of damage determines whether the cell will undergo growth arrest and repair, or initiate apoptosis. Mutations in p53 interfere with this activity, rendering the cell resistant to apoptosis by a wide range of cellular insults. Some progress has been made in understanding the molecular biology of p53, but many questions remain p53 is known to function as a transcription factor, with the ability to positively or negatively regulate the expression of a variety of genes involved in cell cycle control, DNA repair, and apoptosis (including the anti-apoptotic Bcl-2 gene described above and the related pro-apoptotic gene Bax). The drug resistant phenotype conferred by p53 alterations has been linked to Bcl-2/Bax regulation, but this correlation does not hold for most cancer types, leaving open the possibility that other critical genes regulated by p53 remain to be identified. SUMMARY OF THE INVENTION [0010] We have discovered that inhibitor of apoptosis (IAP) protein overexpression is associated with a wide range of cancer types including ovarian cancer, adenocarcinoma, lymphoma, and pancreatic cancer. In addition, we have found that nuclear localization, fragmentation of the IAPs, and overexpression of the IAPs in the presence of p53 mutations correlate with a cancer diagnosis, a poor prognosis, and resistance to numerous chemotherapeutic cancer drugs. These discoveries provide diagnostic, prognostic, and therapeutic compounds and methods for the detection and treatment of proliferative diseases. One way in which the expression of an IAP in a cell can be decreased is by administering to the cell a negative regulator of the IAP apoptotic pathway, for example, an antisense nucleic acid. [0011] In general, the invention features methods and reagents useful for inducing apoptosis in a cell. The methods and reagents of the invention are useful in treating cancers, and other proliferative diseases. [0012] In a first aspect, the invention features an inhibitor of apoptosis (IAP) antisense oligonucleotide that inhibits IAP biological activity, regardless of the length of the antisense oligonucleotide. In preferred embodiments, the IAP is XIAP, HIAP1, or HIAP2. In other preferred embodiments, the antisense oligonucleotide is mammalian, for example, mouse or human. In yet another embodiment, the antisense oligonucleotide is between 8 and 30 nucleotides in length. [0013] In still other further preferred embodiments, the XIAP antisense is chosen from any one of SEQ ID NOS: 1 through 96, and the HIAP1 antisense is chosen from any one of SEQ ID NOS: 97 through 194. Preferably the IAP biological activity is inhibition of apoptosis or inhibition of IAP RNA or polypeptide expression. The antisense oligonucleotide may comprise at least one modified internucleoside linkage. Preferably the modified internucleoside linkage is a phosphorothioate, a methylphosphonate, a phosphotriester, a phosphorodithioate, or a phosphoselenate linkage. In addition, the antisense nucleic acid may comprise at least one modified sugar moiety. Preferably this modified sugar moiety is a 2'-O methoxyethyl group or a 2'-O methyl group. In still another preferred embodiment, the antisense oligonucleotide is a chimeric nucleic acid. Preferably the chimeric oligonucleotide comprises DNA residues linked together by phosphorothioate linkages, and the DNA residues are flanked on each side by at least one 2'-O methyl RNA residue linked together by a phosphorothioate linkage. More preferably the DNA residues are flanked on each side by at least three 2'-O methyl RNA residues. In yet another embodiment, the antisense oligonucleotide is a ribozyme. [0014] In a second aspect, the invention features a method of enhancing apoptosis in a cell by administering to the cell a negative regulator of the IAP-dependent antiapoptotic pathway. In preferred embodiments the negative regulator is an antisense IAP oligonucleotide, an antibody that specifically binds an IAP polypeptide, an IAP polypeptide comprising a ring zinc finger, the polypeptide having no more than two BIR domains, a nucleic acid encoding the ring zinc finger domain of an IAP polypeptide, or a compound that prevents cleavage of the IAP polypeptide. [0015] In preferred embodiments of the second aspect of the invention, the cell is in a mammal diagnosed with a proliferative disease, for example, cancer. The cell may comprise a mucosa-associated lymphoid tissue (MALT), a tissue in which the IAP gene HIAP1 is frequently involved in a translocation, resulting in marginal zone cell lymphomas. The cell may also be a breast cancer cell, where increased HIAP1 expression is known to correlate with tumor progression. The cell may also be a cell in which NFKB expression or activity is increased, for example, cell of head and neck carcinomas, adult T-cell lymphomas, nasopharyngeal carcinomas, and Hodgkin's disease. The cell may also be an acute myelogenous leukemia cell, where increased XIAP levels correlate with poor patient prognosis. In addition, the cell may be a small cell lung carcinoma cell, where increased levels of XIAP correlates with increased resistance to radiation treatment. [0016] In preferred embodiments of the second aspect of the invention, the IAP is XIAP, HIAP1, or HIAP2. Preferably the antisense oligonucleotide is mammalian, for example, mouse or human. In still other preferred embodiments, the XIAP antisense oligonucleotide is chosen from any one of SEQ ID NOS: 1 through 96, and the HIAP1 antisense oligonucleotide is chosen from any one of SEQ ID NOS: 97 through 194. [0017] In still other embodiments of the second aspect of the invention, the antisense oligonucleotide comprises at least one modified internucleoside linkage. Preferably the modified internucleoside linkage is a phospborothioate, a methyiphosphonate, a phosphotriester, a phosphorodithioate, or a phosphoselenate linkage. In addition, the antisense oligonucleotide may comprise at least one modified sugar moiety. Preferably this modified sugar moiety is a 2'-O methoxyethyl group or a 2'-O methyl group. In still another preferred embodiment, the antisense oligonucleotide is a chimeric nucleic acid. Preferably the chimeric oligonucleotide comprises DNA residues linked together by phosphorothioate linkages, and the DNA residues are flanked on each side by at least one 2'-O methyl RNA residue linked together by a phosphorothioate linkage. More preferably the DNA residues are flanked on each side by at least three 2'-O methyl RNA residues. In still further embodiments, administration of the antisense oligonucleotide sensitizes the cell to chemotherapy or radiotherapy. In addition, the cell may be in vitro or in vivo. [0018] In a third aspect, the invention features a pharmaceutical composition comprising a mammalian IAP antisense oligonucleotide. In one preferred embodiment, the mammalian antisense IAP oligonucleotide is a human antisense nucleic acid. Preferably the antisense oligonucleotide binds a target sequence of the human XIAP gene or mRNA, the human HIAP1 gene or mRNA, the human HIAP2 gene or mRNA, the murine XIAP gene or mRNA, the murine HIAP1 gene or mRNA, or the mu rine HIAP2 gene or mRNA. More preferably the composition comprises an antisense oligonucleotide chosen from any one of SEQ ID NOS: 1 through 96 (XIAP) or SEQ ID NOS: 97 through 194 (HIAP1). [0019] In another aspect, the invention features an IAP gene nucleic acid fragment or antisense RNA sequence for use in suppressing cell proliferation. Such nucleic acids of the invention and methods for using them may be identified according to a method involving: (a) providing a cell sample; (b) introducing by transformation into the cell sample a candidate IAP nucleic acid; (c) expressing the candidate IAP nucleic acid within the cell sample; and (d) determining whether the cell sample exhibits an altered apoptotic response, whereby decreased apoptosis identifies an anti-proliferative compound. Preferably the cell is a cancer cell. [0020] In another aspect, the invention features a method of treating a patient diagnosed with a proliferative disease. In the method, apoptosis may be induced in a cell to control a proliferative disease either alone or in combination with other therapies by administering to the cell a negative regulator of the IAP-dependent or anti-apoptotic pathway. The negative regulator may be, but is not limited to, an IAP ring zinc finger, and an IAP polypeptide that includes a ring zinc finger and lacks at least one BIR domain. Alternatively, apoptosis may be induced in the cell by administering an oligonucleotide encoding an IAP antisense RNA molecule administered directly or via gene therapy (see U.S. Pat. No. 5,576,208 for general parameters that may be applicable in the selection of IAP antisense RNAs). Continue reading about Antisense iap oligonucleotides and uses thereof... Full patent description for Antisense iap oligonucleotides and uses thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Antisense iap oligonucleotides and uses thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Antisense iap oligonucleotides and uses thereof or other areas of interest. ### Previous Patent Application: Compositions useful for reducing nephrotoxicity and methods of use thereof Next Patent Application: Chemically modified oligonucleotides for use in modulating micro rna and uses thereof Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Antisense iap oligonucleotides and uses thereof patent info. IP-related news and info Results in 0.2425 seconds Other interesting Feshpatents.com categories: Novartis , Pfizer , Philips , Polaroid , Procter & Gamble , 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
