Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-04-09
2001-08-21
LeGuyader, John L. (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S252300, C435S320100, C435S325000, C536S023100, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06277574
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to nine genes associated with diseases of the kidney as identified by their coexpression with genes known to be associated with renal disorders. The invention also relates to polypeptides encoded by these genes and to the use of these amino acid and nucleic acid sequences in the diagnosis, prognosis, prevention, treatment, and evaluation of therapies for diseases of the kidney.
BACKGROUND OF THE INVENTION
The kidneys excrete waste and contribute to maintenance of homeostasis by regulating blood pH, electrolyte levels and blood pressure. Renal failure or dysfunction is the cause of several diseases whose clinical manifestations are typically hyper- or hypo-tension. These diseases include Bartter's syndrome, Gitelman syndrome, autosomal dominant polycystic kidney disease, and nephrolithiasis.
Treatment with antibiotics such as gentamicin, tobramycin, or amikacin can lead to tubular necrosis with consequent risk of acute renal failure in as much as 25% of patients. A cumulative dose of 2 to 3 grams amphotericin B is likewise nephrotoxic. Cyclosporine, an immunosuppressant given to organ transplant patients, is also nephrotoxic. The molecular basis for the nephrotoxicity of these and other compounds is not understood, although calbindin D levels appear to be a useful diagnostic marker signaling cyclosporine-induced nephrotoxicity (Aicher et al. (1998) Electrophoresis 19:1998-2003). Similarly, reductions in urinary excretion of proteins such as Tamm-Horsfall protein, beta 2 microglobin, and urinary retinol binding protein, appear to be diagnostic for nephrctoxicity when induced by certain chemotherapeutic agents including ifosfamide and cisplatinum (MacLean et al. (1998) Cancer Chemother. Pharmacol. 41:413-6; Tokuc et al. (1997) J. Exp. Clin. Cancer Res. 16:227-30).
We have identified nine novel kidney disease-associated genes through their co-expression with genes known to affect kidney function in normal and diseased states. The present invention satisfies a need in the art by providing new amino acid and nucleic acid compositions that are useful for diagnosis, prognosis, treatment, prevention, and evaluation of therapies for renal disorders.
SUMMARY OF THE INVENTION
In one aspect, the invention provides for a substantially purified polynucleotide comprising a gene that is coexpressed with one or more known kidney disease-associated genes in a plurality of biological samples. Preferably, known kidney disease-associated genes are selected from the group consisting of uromodulin, NKCC2 (bumetanide-sensitive Na—K—Cl cotransporter 2), NCCT (thiazine-sensitive Na—Cl cotransporter), aldolase B, ROMK1 (inwardly-rectifying voltage-gated K channel), ATP1G1 (Na—K ATPase gamma subunit), PDZK1 (PDZ domain-containing protein), NPT-1 (Na-dependent phosphate cotransporter), calbindin, kininogen, and CIC-Kb (chloride channel). Preferred embodiments include (a) a polynucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9 (SEQ ID NO: 1-5and 7-9); (b) a polynucleotide sequence which encodes a polypeptide sequence selected from the group consisting of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12 (SEQ ID NO:10-12); (c) a polynucleotide sequence having at least 75% identity to the polynucleotide sequence of (a) or (b); (d) a polynucleotide sequence which is complementary to the polynucleotide sequence of (a), (b), or (c); (e) a polynucleotide sequence comprising at least 10, preferably at least 18, sequential nucleotides of the polynucleotide sequence of (a), (b), (c), or (d); or (f) a polynucleotide which hybridizes under stringent conditions to the polynucleotide of (a), (b), (c), (d), or (e). Furthermore, the invention provides an expression vector comprising any of the above described polynucleotides, and a host cell containing the expression vector. Still further, the invention provides a method for treating or preventing a disease or condition associated with the altered expression of a gene that is coexpressed with one or more known kidney disease-associated genes comprising administering to a subject in need a polynucleotide described above in an amount effective for treating or preventing the disease.
In a second aspect, the invention provides a substantially purified polypeptide comprising the gene product of a gene that is coexpressed with one or more known kidney disease-associated genes in a plurality of biological samples. The known kidney disease-associated gene may be selected from the group consisting of uromodulin, NKCC2, NCCT, aldolase B, ROMK1, ATP1G1, PDZK1, NPT-1, calbindin, kininogen, and CIC-Kb. Preferred embodiments are (a) the polypeptide sequence selected from the group consisting of SEQ ID NO:10-12; (b) a polypeptide sequence having at least 85% identity to the polypeptide sequence of (a); and (c) a polypeptide sequence comprising at least 6 sequential amino acids of the polypeptide sequence of (a) or (b). Additionally, the invention provides antibodies that bind specifically to any of the above described polypeptides and a method for treating or preventing a disease or condition associated with the altered expression of a gene that is coexpressed with one or more known kidney disease-associated genes comprising administering to a subject in need such an antibody in an amount effective for treating or preventing the disease.
In another aspect, the invention provides a pharmaceutical composition comprising the polynucleotide of claim
2
or the polypeptide of claim
3
in conjunction with a suitable pharmaceutical carrier and a method for treating or preventing a disease or condition associated with the altered expression of a gene that is coexpressed with one or more known kidney disease-associated genes comprising administering to a subject in need such a composition in an amount effective for treating or preventing the disease.
In a further aspect, the invention provides a method for diagnosing a disease or condition associated with the altered expression of a gene that is coexpressed with one or more known kidney disease-associated genes, wherein each known kidney disease-associated gene is selected from the group consisting of uromodulin, NKCC2, NCCT, aldolase B, ROMK1, ATP1G1, PDZK1, NPT-1, calbindin, kininogen, and CIC-Kb. The method comprises the steps of (a) providing a sample comprising one or more of the coexpressed genes; (b) hybridizing the polynucleotide of claim
2
to the coexpressed genes under conditions effective to form one or more hybridization complexes; (c) detecting the hybridization complexes; and (d) comparing the levels of the hybridization complexes with the level of hybridization complexes in a nondiseased sample, wherein altered levels of one or more of the hybridization complexes in a diseased sample compared with the level of hybridization complexes in a non-diseased sample correlates with the presence of the disease or condition.
Additionally, the invention provides antibodies, antibody fragments, and immunoconjugates that exhibit specificity to any of the above described polypeptides and methods for treating or preventing diseases or conditions of the kidney.
BRIEF DESCRIPTION OF THE SEQUENCE LISTING
The Sequence Listing provides exemplary kidney disease-associated gene sequences including polynucleotide sequences, SEQ ID NO:1-9, and the polypeptide sequences, SEQ ID NO:10-12. Each sequence is identified by a sequence identification number (SEQ ID NO) and by the Incyte clone number with which the sequence was first identified.
DESCRIPTION OF THE INVENTION
It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a host cell” includes a plurality of such host cells, and a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
Definitions
“NSEQ”
Azimzai Yalda
Klingler Tod M.
Volkmuth Wayne
Walker Michael G.
Yue Henry
Epps Janet
Incyte Genomics Inc.
Incyte Genomics, Inc.
LeGuyader John L.
Murry, PhD Lynn E.
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