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WO2004086047A2 - Agents diagnostiques et therapeutiques de maladies associees a adenosine a1 du recepteur couple a la proteine g (adora1) - Google Patents

Agents diagnostiques et therapeutiques de maladies associees a adenosine a1 du recepteur couple a la proteine g (adora1) Download PDF

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Publication number
WO2004086047A2
WO2004086047A2 PCT/EP2004/002734 EP2004002734W WO2004086047A2 WO 2004086047 A2 WO2004086047 A2 WO 2004086047A2 EP 2004002734 W EP2004002734 W EP 2004002734W WO 2004086047 A2 WO2004086047 A2 WO 2004086047A2
Authority
WO
WIPO (PCT)
Prior art keywords
disorders
adoral
diseases
polypeptide
hormone
Prior art date
Application number
PCT/EP2004/002734
Other languages
English (en)
Other versions
WO2004086047A3 (fr
Inventor
Stefan Golz
Ulf Brüggemeier
Andreas Geerts
Ralf Thiele
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 WO2004086047A2 publication Critical patent/WO2004086047A2/fr
Publication of WO2004086047A3 publication Critical patent/WO2004086047A3/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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the nucleic acid polymerase displaces a portion of the 5' end of the probe and through its nuclease activity cleaves mononucleotides or oligonucleotides from the probe.
  • PCR-based methods can be used to extend nucleic acid sequences encoding human ADORAl, for example to detect upstream sequences of ADORAl gene such as promoters and regulatory elements.
  • restriction-site PCR uses universal primers to retrieve unknown sequence adjacent to a known locus. Genomic DNA is first amplified in the presence of a primer to a linker sequence and a primer specific to the known region. The amplified sequences are then subjected to a second round of PCR with the same linker primer and another specific primer internal to the first one. Products of each round of PCR are transcribed with an appropriate RNA polymerase and sequenced using reverse transcriptase.
  • a variety of protocols for detecting and measuring the expression of ADORAl, using either polyclonal or monoclonal antibodies specific for the polypeptide, are known in the art. Examples include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence activated cell sorting (FACS).
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • FACS fluorescence activated cell sorting
  • a two- site, monoclonal-based immunoassay using monoclonal antibodies reactive to two non-interfering epitopes on ADORAl can be used, or a competitive binding assay can be employed.
  • Antibodies according to the invention can be purified by methods well known in the art. For example, antibodies can be affinity purified by passage over a column to which ADORAl is bound. The bound antibodies can then be eluted from the column using a buffer with a high salt concentration.
  • the methods entail the identification of candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other molecules) which bind to ADORAl and/or have a stimulatory or inhibitory effect on the biological activity of ADORAl or its expression and then determining which of these compounds have an effect on symptoms or diseases regarding the hematological and cardiovascular diseases, disorders of the peripheral and central nervous system, COPD, asthma, genito- urological disorders and inflammation diseases in an in vivo assay.
  • candidate or test compounds or agents e.g., peptides, peptidomimetics, small molecules or other molecules
  • reporter gene e.g., LacZ
  • a reporter gene e.g., LacZ
  • Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the DNA sequence encoding the protein which interacts with ADORAl.
  • microarray refers to an array of distinct polynucleotides or oligonucleotides arrayed on a substrate, such as paper, nylon or any other type of membrane, filter, chip, glass slide, or any other suitable solid support.
  • a ADORAl polynucleotide is contacted with a test compound, and the expression of an RNA or polypeptide product of ADORAl polynucleotide is determined ⁇
  • the level of expression of appropriate mRNA or polypeptide in the presence of the test compound is compared to the level of expression of mRNA or polypeptide in the absence of the test compound.
  • the test compound can then be identified as a regulator of expression based on this comparison.
  • ADORAl is expressed in various human tissues.
  • the expression in brain tissues and in particular the differential expression between diseased tissue Alzheimer brain and healthy tissue brain, between diseased tissue Alzheimer brain cerebellum and healthy tissue , between diseased tissue Alzheimer cerebral cortex and healthy tissue cerebral cortex demonstrates that the human adenosine al or mRNA can be utilized to diagnose nervous system diseases. Additionally the activity of the human adenosine al can be modulated to treat nervous system diseases.
  • Ischemic diseases are conditions in which the coronary flow is restricted resulting in a perfusion which is inadequate to meet the myocardial requirement for oxygen.
  • This group of diseases includes stable angina, unstable angina and asymptomatic ischemia.
  • Arrhythmias include all forms of atrial and ventricular tachyarrhythmias, atrial tachycardia, atrial flutter, atrial fibrillation, atrio-ventricular reentrant tachycardia, preexitation syndrome, ventricular tachycardia, ventricular flutter, ventricular fibrillation, as well as bradycardic forms of arrhythmias.
  • Hypertensive vascular diseases include primary as well as all kinds of secondary arterial hypertension, renal, endocrine, neurogenic, others.
  • the genes may be used as drug targets for the treatment of hypertension as well as for the prevention of all complications arising from cardiovascular diseases.
  • Cardiovascular diseases include but are not limited to disorders of the heart and the vascular system like congestive heart failure, myocardial infarction, ischemic diseases of the heart, all kinds of atrial and ventricular arrhythmias, hypertensive vascular diseases, peripheral vascular diseases, and atherosclerosis.
  • Disorders according to 6) include, but are not limited to acute myeloic leukemia, acute lymphoblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome.
  • Disorders according to 7) include, but are not limited to Hodgkin's disease, non-Hodgkin's lymphoma, Burkitt's lymphoma, mycosis fungoides cutaneous T-cell lymphoma.
  • Disorders according to 8) include, but are not limited to multiple myeloma, macroglobulinemia, heavy chain diseases.
  • the human adenosine al is highly expressed in the following tissues of the hematological system: neutrophils peripheral blood, spleen liver cirrhosis.
  • the expression in the above mentioned tissues and in particular the differential expression between diseased tissue spleen liver cirrhosis and healthy tissue spleen demonstrates that the human adenosine al or mRNA can be utilized to diagnose of hematological diseases. Additionally the activity of the human adenosine al can be modulated to treat hematological disorders.
  • Thyroiditis are silent lymphocytic thyroiditis, Hashimoto's thyroiditis, or subacute granulomatous thyroiditis.
  • Metabolic diseases often are caused by single defects in particular biochemical pathways, defects that are due to the deficient activity of individual enzymes or molecular receptors leading to the regulation of such enzymes. Hence in a broader sense disturbances of the underlying genes, their products and their regulation lie well within the scope of this definition of a metabolic disease.
  • metabolic diseases according to 7 comprise sexual dysfunction of the male and female.
  • metabolic diseases according to 8) comprise confused states and seizures due to inappropriate secretion of antidiuretic hormone from the pituitary gland, Liddle's syndrome, Bartter's syndrome, Fanconi's syndrome, renal electrolyte wasting, diabetes insipidus.
  • Stimulation of activity or expression of ADORAl is desirable in situations in which activity or expression is abnormally low and in which increased activity is likely to have a beneficial effect. Conversely, inhibition of activity or expression of
  • An antagonist of ADORAl may be produced using methods which are generally known in the art.
  • purified ADORAl may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind ADORAl.
  • Antibodies to ADORAl may also be generated using methods that are well known in the art.
  • Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies like those which inhibit dimer formation are especially preferred for therapeutic use.
  • the polynucleotides encoding ADORAl, or any fragment or complement thereof may be used for therapeutic purposes.
  • the complement of the polynucleotide encoding ADORAl may be used in situations in which it would be desirable to block the transcription of the mRNA.
  • cells may be transformed with sequences complementary to polynucleotides encoding ADORAl.
  • complementary molecules or fragments may be used to modulate ADORAl activity, or to achieve regulation of gene function.
  • sense or antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding ADORAl.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • the polynucleotides encoding ADORAl may be used for diagnostic purposes.
  • the polynucleotides which may be used include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs.
  • the polynucleotides may be used to detect and quantitate gene expression in biopsied tissues in which expression of ADORAl may be correlated with disease.
  • the diagnostic assay may be used to distinguish between absence, presence, and excess expression of ADORAl, and to momtor regulation of ADORAl levels during therapeutic intervention.
  • Another object of the invention is a method of the above, wherein the contacting step is in or at the surface of a cell.
  • highest CT cor-cD NA-n ⁇ 40 is defined as CT cor- cDNA [high]
  • modifications of gene expression is obtained by designing antisense sequences to intron regions, promoter/enhancer elements, or even to transacting regulatory genes.
  • the vector contains promoters or enhancers which increase gene expression.
  • promoters are host specific and include MMTV, SV40, and metallothionine promoters for CHO cells; trp, lac, tac and T7 promoters for bacterial hosts; and alpha factor, alcohol oxidase and PGH promoters for yeast.
  • Transcription enhancers such as the rous sarcoma virus enhancer, are used in mammalian host cells. Once homogeneous cultures of recombinant cells are obtained through standard culture methods, large quantities of recombinantly produced ADORAl are recovered from the conditioned medium and analyzed using chromatographic methods known in the art.
  • selected peptides typically, about 15 residues in length, are synthesized using an Applied Biosystems Peptide Synthesizer Model 431 A using finoc-chemistry and coupled to keyhole limpet hemocyanin (KLH; Sigma, St. Louis, MO) by reaction with M-maleimidobenzoyl-N-hydroxysuccinimide ester, MBS. If necessary, a cysteine is introduced at the N-terminus of the peptide to permit coupling to KLH. Rabbits are immunized with the peptide-KLH complex in complete Freund's adjuvant.
  • KLH keyhole limpet hemocyanin
  • 10 8 M “1 preferably 10 9 to 10 10 M "1 or stronger, are typically made by standard procedures.
  • the anti-id is then used to identify and isolate peptides from banks of chemically or biologically produced peptides.
  • the isolated peptides then act as the pharmacore.
  • LSTs are delivered by known routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol; transdermal patch and bandage; injectable, intravenous and lavage formulations; and orally administered liquids and pills particularly formulated to resist stomach acid and enzymes.
  • routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol; transdermal patch and bandage; injectable, intravenous and lavage formulations; and orally administered liquids and pills particularly formulated to resist stomach acid and enzymes.
  • the particular formulation, exact dosage, and route of administration is determined by the attending physician and varies according to each specific situation.
  • Animal model systems which elucidate the physiological and behavioral roles of the ADORAl are produced by creating nonhuman transgenic animals in which the activity of the ADORAl is either increased or decreased, or the amino acid sequence of the expressed ADORAl is altered, by a variety of techniques.
  • these techniques include, but are not limited to: 1) Insertion of normal or mutant versions of DNA encoding a ADORAl, by microinjection, electroporation, retroviral transfection or other means well known to those skilled in the art, into appropriately fertilized embryos in order to produce a transgenic animal or 2) homologous recombination of mutant or normal, human or animal versions of these genes with the native gene locus in transgenic animals to alter the regulation of expression or the structure of these ADORAl sequences.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • Endocrinology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une ADORA1 humaine associée aux maladies cardio-vasculaires, aux maladies du système endocrinien et hormonal, aux maladies du métabolisme, aux maladies hématologiques, respiratoires, neurologiques ou urologiques. Elle concerne également des méthodes servant à identifier des composés utiles pour le traitement ou la prophylaxie de maladies cardio-vasculaires, de maladies du système endocrinien et hormonal, de maladies du métabolisme, de maladies hématologiques, respiratoires, neurologiques ou urologiques. Elle concerne également des composés se fixant à ADORA1 et/ou activant ou inhibant cette activité, ainsi que des compositions pharmaceutiques contenant ces composés.
PCT/EP2004/002734 2003-03-28 2004-03-17 Agents diagnostiques et therapeutiques de maladies associees a adenosine a1 du recepteur couple a la proteine g (adora1) WO2004086047A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03006847 2003-03-28
EP03006847.2 2003-03-28

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WO2004086047A2 true WO2004086047A2 (fr) 2004-10-07
WO2004086047A3 WO2004086047A3 (fr) 2005-01-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023150541A1 (fr) * 2022-02-01 2023-08-10 The Uab Research Foundation Agent anticonvulsivant et neuroprotecteur
WO2024215814A3 (fr) * 2023-04-10 2024-11-21 Anand Rene Procédés et compositions pharmaceutiques pour le traitement du vieillissement

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817760A (en) * 1992-03-13 1998-10-06 Merck & Co., Inc. Human A3 adenosine receptors
ES2120025T3 (es) * 1993-02-26 1998-10-16 Merrell Pharma Inc Derivados de xantina utilizados como antagonistas de receptores de adenosina a1.
US6492377B1 (en) * 1998-06-25 2002-12-10 Boehringer Ingelheim Pharma Kg Imidazotriazolopyrimidines with adenosine-antagonistic activity
EP1386004A4 (fr) * 2001-04-05 2005-02-16 Ribozyme Pharm Inc Modulation de l'expression genique associee a la proliferation inflammatoire et a la croissance de neurites, par des procedes faisant intervenir l'acide nucleique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023150541A1 (fr) * 2022-02-01 2023-08-10 The Uab Research Foundation Agent anticonvulsivant et neuroprotecteur
WO2024215814A3 (fr) * 2023-04-10 2024-11-21 Anand Rene Procédés et compositions pharmaceutiques pour le traitement du vieillissement

Also Published As

Publication number Publication date
WO2004086047A3 (fr) 2005-01-20

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