Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-06-26
2001-11-27
Zeman, Mary K. (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023500, C536S024300, C435S006120, C435S069100, C435S069300, C435S320100, C514S04400A
Reexamination Certificate
active
06323329
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the fields of molecular biology and biotechnology. More specifically, the invention relates to compositions and methods based on DNA sequences of MAG genes or of genes of the high mobility group proteins and substances for: (1) treatment of diseases; (2) contraception; and (3) tissue generation. Corresponding kits and methods also are disclosed.
BACKGROUND OF THE INVENTION
When studying the molecular basis of aberrant cell growth that accompanies the growth of benign and malignant tumors, so-called MAG genes (multiple-tumor aberration growth genes) were identified as belonging to the group to which high mobility group protein (HMG genes) genes belong.
The genes of the high mobility group proteins, such as the HMGI-C gene located on the human chromosome 12 and the HMGI-Y gene on chromosome 6, which, among the known HMG genes, has the relative highest homologous degree compared to HMGI-C, usually have components that code for DNA-bonding protein parts and components that code for protein-bonding components.
Studies by Schoenmakers et al., (
Nature Genet
10:436 (1995)) studies show that mutations of the HMGI-C gene are the most likely cause of the development of many benign human tumors, some groups of which are: uterus leiomyoma, lipoma, pleomorphic adenoma of the salivary gland, endometrium polyps, harnarto chondroma of the lung, aggressive angiomyxoma, and fibroadenoma of the mamma.
With the exception of the pleomorphic adenoma, all of the above tumors are of mesenchymal origin or contain mesenchymal components that are considered to be monoclonal. Today the pleomorphic adenoma is mostly considered to be an epithelial tumor, although its histogenesis still has not been completely determined and there are discussions concerning the participation of mesenchymalic cells in the development of tumors. Many of the tumors sometimes or even regularly show mesenchymalic metaplasia. Also striking is the appearance of myxoid cartilage in many of the tumors, which is characteristic of hamarto chondroma of the lung and the pleomorphic adenoma, for example. Ashar et al., (
Cell
82:57 (1995)) confirmed the findings of Schoeniakers et al., (
Nature Genet
10:436 (1995)) for the lipoma group.
Definitions
As used herein, it is to be understood that “HMGI genes” refers to a subfamily of high mobility group protein genes comprising HMGI-C and HMGI(Y). Furthermore, the respective translation products comprise HMGI-C encoded by the HMGI-C gene, and HMGI and HMGY both encoded by the HMGI(Y) gene.
SUMMARY OF THE INVENTION
A first aspect of the invention relates to an isolated polynucleotide having a sequence that includes a first sequence encoding each of exons 1, 2 and 3 of an HMGI or MAG gene, and a second sequence from a source other than an HMGI or MAG gene, wherein the second sequence is a human DNA sequence which is a sequence other than a sequence immediately upstream of exon 1 of the HMGI or MAG gene in a human genome. According to one embodiment of the invention, the second sequence of the isolated polynucleotide encodes a gene product which is encoded by one of SEQ ID NOS:1-19. According to another embodiment of the invention, the isolated polynucleotide has the sequence of one of SEQ ID NOS:1-19.
A second aspect of the invention relates to an isolated polypeptide having a sequence that includes a first sequence encoded by exons 1, 2 and 3 of an HMGI or MAG gene, and a second sequence encoded by a polynucleotide from a source other than an HMGI or MAG gene. The second polynucleotide is from a human, but has a sequence other than the sequence located immediately upstream of exon 1 of the HMGI or MAG gene in the human genome. According to one embodiment of the invention, the isolated polypeptide has a sequence encoded by one of SEQ ID NOS:1-19.
A third aspect of the invention relates to a method for treating tumors in a mammal. This method includes the steps of administering to the mammal an agent which blocks the activity or effect of a DNA selected from the group consisting of an HMGI gene, a MAG gene and a polynucleotide having a sequence which includes at least a first sequence encoding each of exons 1, 2 and 3 of an HMGI or MAG gene; and a second sequence which is from a source other than an HMGI or MAG gene. This second sequence is a human DNA sequence and is a sequence other than the sequence immediately upstream of exon 1 of the HMGI or MAG gene in the human genome. According to one embodiment the DNA has a sequence of one of SEQ ID NOS:1-19 or a sequence encoding the same amino acids encoded by SEQ ID NOS:1-19. Alternatively, agent inhibits the formation of transcripts of the HMGI or MAG genes. According to another embodiment, the agent decreases the half-life of the HMGI or MAG gene transcripts. According to yet another embodiment, the agent is selected from the group consisting of anti-sense nucleic acid molecules and ribozymes. According to still yet another embodiment, the agent is a translation product of the DNA molecule. According to a further embodiment, the administering step involves incorporating the agent into the tumor. This administering step can include introducing a vector to the tumor, where this vector includes the DNA or an RNA transcript thereof, and then expressing the DNA or RNA transcript to create translation products thereof which competitively inhibit binding of cellular HMGI/MAG gene translation products to the cellular genome. According to a different embodiment, the tumor is one which shows expression of a gene which is selected from the group consisting of HMGI genes, HMGI-C genes and HMGI-Y genes. In the alternative, the agent can be a nucleic acid having a sequence that includes at least one AT hook or at least one AT hook-like structure.
A fourth aspect of the invention relates to a method for diagnosing of tumors which includes the steps of: (1) administering to suspected tumor tissue a first polynucleotide which is complementary to a second polynucleotide that is selected from the group consisting of HMGI genes, MAG genes and nucleic acid molecules having sequences according to one of SEQ ID NOS.: 1-19; and (2) detecting significant complex formation between the first polynucleotide and the second polynucleotide when a tumor is present, but not when a tumor is absent. In this instance, the first polynucleotide additionally may include a marker or label.
A fifth aspect of the invention relates to a method for diagnosing tumors which includes the steps of: (1) administering to suspected tumor tissue a translation product of a polynucleotide selected from the group consisting of HMGI genes, MAG genes and nucleic acid molecules having sequences according to one of SEQ ID NOS.: 1-19; and then (2) detecting significant complex formation between the product and the polynucleotide when a tumor is present, but not when a tumor is absent. In a preferred embodiment of this method, the translation product includes a marker or label.
A sixth aspect of the invention relates to a method for diagnosing of tumors that involves the steps of: (1) administering to suspected tumor tissue an antibody to a translation product of a polynucleotide selected from the group consisting of HMGI genes, MAG genes and nucleic acid molecules having sequences according to one of SEQ ID NOS.: 1-19; and then (2) detecting significant complex formation between the antibodies and the translation products when a tumor is present, but not when a tumor is absent. In one embodiment of the invented method the antibody is selected from the group consisting of polyclonal antibodies, monoclonal antibodies and fragments and derivatives thereof. In a different embodiment the antibody includes a marker or label.
A seventh aspect of the invention relates to a method for diagnosis of endometriosis which involves: (1) administering a first polynucleotide to suspected ectopic endometrial tissue complementary to a second polynucleotide which is selected from the group consisting of HMGI genes, MAG genes and nucleic acid molecules having sequence
Knobbe Martens Olson & Bear LLP
Zeman Mary K.
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