Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-01-15
2002-04-09
Fredman, Jeffrey (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S022100, C536S023100, C536S024500
Reexamination Certificate
active
06368794
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to polynucleotides comprising at least a fragment of genes that regulate cell proliferation and methods comprising the use of such polynucleotides.
BACKGROUND OF THE INVENTION
Cellular proliferation in normal tissues is strictly regulated by multiple factors and mechanisms. Cells grow and differentiate, carry out their structural or metabolic roles, participate in organismal development, and respond to their environment by altering their gene expression. Cellular functions are controlled by the timing and the amount of expression attributable to thousands of individual genes.
Aberrant cellular proliferation can be the result of under- or overexpression of genes which regulate cell growth, differentiation, and metastasis. Overexpression of oncogenes, which include growth factors, growth factor receptors, transcriptional activators, proteases, cell matrix components and other proteins necessary for cell growth regulation, can result in aberrant cell proliferation. Conversely, underexpression of regulatory proteins, inhibitors or suppressor of oncogenes, cell cycle regulators, and apoptosis inducers may contribute to abnormal cell proliferation. In many cases of aberrant cellular proliferation changes in expression of multiple factors contribute to the development of cell growth disorders such as cancers.
The present invention identifies particular polynucleotides that can be used to detect the altered expression of genes that regulate cell proliferation and consequently, diagnose diseases involving aberrant cell proliferation, such as cancer. The polynucleotides may also be used to treat such diseases.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a composition comprising one or more polynucleotides, wherein each of said polynucleotides comprises at least a fragment of a gene implicated in the regulation of cell proliferation. The plurality of polynucleotides can be selected from I) first polynucleotides, wherein each of said first polynucleotides comprises at least a fragment of a gene differentially expressed in precancerous biological samples; or II) second polynucleotides, wherein each of said second polynucleotides comprises at least a fragment of a gene differentially expressed in cancerous biological samples. The composition is useful for the detection of the altered expression of genes that regulate cell proliferation.
Generally, first polynucleotide sequences are selected by a first method comprising a) preparing more than one first, second and third transcript profiles from noncancerous, precancerous and cancerous biological samples, respectively; b) comparing said first, second and third transcript profiles to detect a plurality of genes that are differentially expressed in either noncancerous, precancerous and cancerous biological samples, respectively; and c) identifying one of said detected genes that are differentially expressed in precancerous biological samples. Second polynucleotide sequences are selected by a second method comprising a) preparing more than one first, second and third transcript profiles from noncancerous, precancerous and cancerous biological samples, respectively; b) comparing said first, second and third transcript profiles to detect a plurality of genes that are differentially expressed in either noncancerous, precancerous and cancerous biological samples, respectively; and c) identifying one of said detected genes that are differentially expressed in cancerous biological samples. The polynucleotides may be complementary DNAs (cDNAs), genomic DNA fragments, oligonucleotides and the like.
In one preferred embodiment, the composition comprises a polynucleotide comprising a sequence selected from the group consisting of: a) a polynucleotide sequence selected from the group consisting of SEQ ID NOs:1-16; b) a polynucleotide sequence, comprising a polynucleotide sequence which encodes the polypeptide sequence selected from the group consisting of: of SEQ ID NOs:17-23; c) a polynucleotide sequence having at least 70% identity to the polynucleotide sequence of (a) or (b); (d) a polynucleotide sequence comprising at least 18 sequential nucleotides of the polynucleotide sequence of (a), (b) or (c); e) a polynucleotide sequence which is complementary to the polynucleotide sequence of (a), (b),(c) or (d); and f) a polynucleotide which hybridizes under stringent conditions to the polynucleotide of (a),(b), (c), (d) or (e).
The composition is particularly useful as hybridizable array elements in a microarray for monitoring the expression of a plurality of sample polynucleotides implicated in the regulation of cell proliferation. The microarray can be used, for example, in the prognosis, diagnosis and treatment of a cancer or other disease relating to the altered expression of genes involved in cell proliferation.
In yet another aspect, the present invention provides a method for identifying polynucleotides for diagnosing, prognosing, or monitoring the progression of cancer or other diseases relating to the altered expression of genes involved in the regulation of cell proliferation. The method comprises selecting first polynucleotide sequences that comprise at least a fragment of genes differentially expressed in precancerous biological samples and second polynucleotide sequences that comprise at least a fragment of genes differentially expressed in cancerous biological samples.
Further, the present invention provides a method for diagnosing, prognosing, or monitoring the treatment of a disease. The method comprises using the composition described above comprising polynucleotide sequences to detect hybridization complexes formed between the polynucleotide sequences and sample polynucleotides. The sample polynucleotides may be from diseased, asymptomatic or nondiseased samples. The polynucleotides are contacted with a sample containing sample polynucleotides under conditions effective to form hybridization complexes between said polynucleotide sequences and sample genes that regulate cell proliferation. Hybridization complexes are then detected. The levels of hybridization complexes in diseased or nonsymptomatic samples are then compared with those in nondiseased samples.
In another aspect, the invention is a polypeptide comprising a sequence selected from the group consisting of: a) a polypeptide sequence selected from the group consisting of SEQ ID NOs:17-23; b) a polypeptide sequence having at least 70% identity to the polypeptide sequence of (a); c) a polypeptide sequence comprising at least 10 sequential amino acids of the polypeptide sequence of (a) or (b).
In another aspect, the invention entails a pharmaceutical composition comprising a polynucleotide or polypeptide in conjunction with a suitable pharmaceutical carrier and a method for treating or preventing a disease or condition associated with the altered expression of genes that regulate cell proliferation comprising administering to a subject in need such a composition in an amount effective for treating or preventing said disease.
In a further aspect, the invention provides a ribozyme that cleaves a gene whose altered expression correlates with a disease associated with cell proliferation and a method for treating or preventing a disease or condition associated with the altered expression of genes that regulate cell proliferation. The method comprises administering to a subject in need the ribozyme in an amount effective for treating or preventing said disease.
In yet another aspect, the invention provides an antisense molecule that hybridizes to a gene whose altered expression correlates with a disease associated with cell proliferation and a method for treating or preventing a disease or condition associated with the altered expression of genes that regulate cell proliferation. The method comprises administering to a subject in need the antisense molecule that hybridizes to the gene.
DESCRIPTION OF THE SEQUENCE LISTING AND TABLES
The Sequence Listing is a compilation of exemplary polynucleotide sequences obtain
Daniel Steven
Gilmore James
Stuart Susan G.
Stuve Laura L.
Chakrabarti Arun K.
Fredman Jeffrey
Incyte Genomics Inc.
Incyte Genomics, Inc.
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