WO2005040830A1 - Agents de diagnostic et de traitement des maladies associees au transporteur 3 de cations organiques (orctl3) - Google Patents

Agents de diagnostic et de traitement des maladies associees au transporteur 3 de cations organiques (orctl3) Download PDF

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Publication number
WO2005040830A1
WO2005040830A1 PCT/EP2004/011406 EP2004011406W WO2005040830A1 WO 2005040830 A1 WO2005040830 A1 WO 2005040830A1 EP 2004011406 W EP2004011406 W EP 2004011406W WO 2005040830 A1 WO2005040830 A1 WO 2005040830A1
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WO
WIPO (PCT)
Prior art keywords
diseases
orctl3
polypeptide
cancer
inflammation
Prior art date
Application number
PCT/EP2004/011406
Other languages
English (en)
Inventor
Stefan Golz
Ulf Brüggemeier
Andreas Geerts
Original Assignee
Bayer Healthcare Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Publication of WO2005040830A1 publication Critical patent/WO2005040830A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease

Definitions

  • oligonucleotide is a stretch of nucleotide residues which has a sufficient number of bases to be used as an oligomer, ampli er or probe in a polymerase chain reaction (PCR). Oligonucleotides are prepared from genomic or cDNA sequence and are used to amplify, reveal, or confirm the presence of a similar DNA or RNA in a particular cell or tissue. Oligonucleotides or oligomers comprise portions of a DNA sequence having at least about 10 nucleotides and as many as about 35 nucleotides, preferably about 25 nucleotides.
  • ORCTL3 - encoding nucleotide sequences may be produced. Some of these will only bear minimal homology to the nucleotide sequence of the known and naturally occurring ORCTL3.
  • the invention has specifically contemplated each and every possible variation of nucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the nucleotide sequence of naturally occurring ORCTL3, and all such variations are to be considered as being specifically disclosed.
  • the probe used in such assays is typically a short (about 20-25 bases) oligonucleotide that is labeled with two different fluorescent dyes.
  • the 5' terminus of the probe is attached to a reporter dye and the 3' terminus is attached to a quenching dye, although the dyes could be attached at other locations on the probe as well.
  • the probe is designed to have at least substantial sequence complementarity with the probe binding site. Upstream and downstream PCR primers which bind to flanking regions of the locus are added to the reaction mixture. When the probe is intact, energy transfer between the two fluorophors occurs and the quencher quenches emission from the reporter.
  • the probe is cleaved by the 5' nuclease activity of a nucleic acid polymerase such as Taq polymerase, thereby releasing the reporter from the oligonucleotide-quencher and resulting in an increase of reporter emission intensity which can be measured by an appropriate detector.
  • a nucleic acid polymerase such as Taq polymerase
  • the labeled probe is selected so that its sequence is substantially complementary to a segment of the test locus or a reference locus. As indicated above, the nucleic acid site to which the probe binds should be located between the primer binding sites for the upstream and downstream amplification primers.
  • the labels used for labeling the probes or primers of the current invention and which can provide the signal corresponding to the quantity of amplification product can take a variety of forms.
  • a fluorescent signal is one signal which can be measured.
  • measurements may also be made, for example, by monitoring radioactivity, colorimetry, absorption, magnetic parameters, or enzymatic activity.
  • labels which can be employed include, but are not limited to, fluorophors, chromophores, radioactive isotopes, electron dense reagents, enzymes, and ligands having specific binding partners (e.g., biotin-avidin).
  • ORCTL3 cDNA molecules can be made with standard molecular biology techniques, using ORCTL3 mRNA as a template. ORCTL3 cDNA molecules can thereafter be replicated using molecular biology techniques known in the art. An amplification technique, such as PCR, can be used to obtain additional copies of polynucleotides of the invention, using either human genomic DNA or cDNA as a template.
  • capture PCR which involves PCR amplification of DNA fragments adjacent to a known sequence in human and yeast artificial chromosome DNA.
  • multiple restriction enzyme digestions and ligations also can be used to place an engineered double-stranded sequence into an unknown fragment of the DNA molecule before performing PCR.
  • libraries that have been size-selected to include larger cDNAs. Randomly-primed libraries are preferable, in that they will contain more sequences which contain the 5' regions of genes. Use of a randomly primed library may be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA.
  • Genomic libraries can be useful for extension of sequence into 5' non-transcribed regulatory regions.
  • ORCTL3 polynucleotides can be inserted into an expression vector which contains the necessary elements for the transcription and translation of the inserted coding sequence.
  • Methods which are well known to those skilled in the art can be used to construct expression vectors containing sequences encoding ORCTL3 and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination.
  • Promoters or enhancers derived from the genomes of plant cells e.g., heat shock, RUBISCO, and storage protein genes
  • plant viruses e.g., viral promoters or leader sequences
  • promoters from mammalian genes or from mammalian viruses are preferable. If it is necessary to generate a cell line that contains multiple copies of a nucleotide sequence encoding ORCTL3, vectors based on SV40 or EBV can be used with an appropriate selectable marker.
  • Stable expression is preferred for long-term, high-yield production of recombinant proteins.
  • cell lines which stably express ORCTL3 can be transformed using expression vectors which can contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells can be allowed to grow for 1-2 days in an enriched medium before they are switched to a selective medium.
  • the purpose of the selectable marker is to confer resistance to selection, and its presence allows growth and recovery of cells which successfully express the introduced ORCTL3 sequences.
  • Resistant clones of stably transformed cells can be proliferated using tissue culture techniques appropriate to the cell type. Any number of selection systems can be used to recover transformed cell lines.
  • ORCTL3 can be synthesized, in whole or in part, using chemical methods well known in the art.
  • ORCTL3 itself can be produced using chemical methods to synthesize its amino acid sequence, such as by direct peptide synthesis using solid-phase techniques. Protein synthesis can either be performed using manual techniques or by automation. Automated synthesis can be achieved, for example, using Applied Biosystems 431 A Peptide Synthesizer (Perkin Elmer).
  • fragments of ORCTL3 can be separately synthesized and combined using chemical methods to produce a full-length molecule.
  • Specific ribozyme cleavage sites within a ORCTL3 RNA target can be identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides corresponding to the region of the target RNA containing the cleavage site can be evaluated for secondary structural features which may render the target inoperable. Suitability of candidate ORCTL3 RNA targets also can be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays. The nucleotide sequences shown in SEQ ID NO: 1 and its complement provide sources of suitable hybridization region sequences.
  • the assay can be a binding assay entailing direct or indirect measurement of the binding of a test compound or a known ORCTL3 ligand to ORCTL3.
  • the assay can also be an activity assay entailing direct or indirect measurement of the activity of ORCTL3.
  • the assay can also be an expression assay entailing direct or indirect measurement of the expression of ORCTL3 mRNA or ORCTL3 protein.
  • the various screening assays are combined with an in vivo assay entailing measuring the effect of the test compound on the symptoms of cardiovascular diseases, gastroenterological diseases, cancer, inflammation, metabolic diseases, neurological diseases and urological diseases,.
  • test compound can be enzymatically labelled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.
  • Native or recombinant ORCTL3 is purified by immunoaffinity chromatography using antibodies specific for ORCTL3.
  • an immunoaffinity column is constructed by covalently coupling the anti-TRH antibody to an activated chromatographic resin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Pathology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hospice & Palliative Care (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne un ORCTL3 humain associé aux maladies cardio-vasculaires, aux maladies gastro-entérologiques, au cancer, aux inflammations, aux maladies métaboliques, aux maladies neurologiques et aux maladies urologiques. L'invention concerne également des dosages permettant d'identifier des composés utiles dans le traitement ou la prévention des maladies cardio-vasculaires, des maladies gastro-entérologiques, du cancer, des inflammations, des maladies métaboliques, des maladies neurologiques et des maladies urologiques. L'invention concerne encore des composés se liant au ORCTL3 et/ou activant ledit transporteur ou inhibant son activité, ainsi que des compositions pharmaceutiques contenant lesdits composés.
PCT/EP2004/011406 2003-10-21 2004-10-12 Agents de diagnostic et de traitement des maladies associees au transporteur 3 de cations organiques (orctl3) WO2005040830A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03023851.3 2003-10-21
EP03023851 2003-10-21

Publications (1)

Publication Number Publication Date
WO2005040830A1 true WO2005040830A1 (fr) 2005-05-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008068827A1 (fr) * 2006-12-01 2008-06-12 J-Pharma Co., Ltd. Nouveau transporteur d'ion organique spécifique au rein
WO2015039972A1 (fr) * 2013-09-17 2015-03-26 Bayer Pharma Aktiengegesellschaft Modulateurs de slc22a13

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002099053A2 (fr) * 2001-06-05 2002-12-12 Exelixis, Inc. Slc22a utilises comme modificateurs de la voie p53 et procedes d'utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002099053A2 (fr) * 2001-06-05 2002-12-12 Exelixis, Inc. Slc22a utilises comme modificateurs de la voie p53 et procedes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAIGO YATARO ET AL: "Molecular cloning of a candidate tumor suppressor gene, DLC1, from chromosome 3p21.3", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, BALTIMORE, MD, US, vol. 59, no. 8, 15 April 1999 (1999-04-15), pages 1966 - 1972, XP002207886, ISSN: 0008-5472 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008068827A1 (fr) * 2006-12-01 2008-06-12 J-Pharma Co., Ltd. Nouveau transporteur d'ion organique spécifique au rein
JPWO2008068827A1 (ja) * 2006-12-01 2010-03-11 ジェイファーマ株式会社 腎臓特異性を有する新規な有機イオントランスポーター
WO2015039972A1 (fr) * 2013-09-17 2015-03-26 Bayer Pharma Aktiengegesellschaft Modulateurs de slc22a13

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