WO2004069258A2 - Utilisation de la famille genique sgk pour diagnostiquer et pour traiter la cataracte et le glaucome - Google Patents

Utilisation de la famille genique sgk pour diagnostiquer et pour traiter la cataracte et le glaucome Download PDF

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WO2004069258A2
WO2004069258A2 PCT/EP2004/001048 EP2004001048W WO2004069258A2 WO 2004069258 A2 WO2004069258 A2 WO 2004069258A2 EP 2004001048 W EP2004001048 W EP 2004001048W WO 2004069258 A2 WO2004069258 A2 WO 2004069258A2
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hsgkl
hsgk3
gene
glaucoma
diabetic neuropathy
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PCT/EP2004/001048
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German (de)
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WO2004069258A3 (fr
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Florian Lang
Andreas Busjahn
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Florian Lang
Andreas Busjahn
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Priority to EP04708350A priority Critical patent/EP1663246A2/fr
Priority to MXPA05008394A priority patent/MXPA05008394A/es
Priority to BR0407300-2A priority patent/BRPI0407300A/pt
Priority to JP2006501737A priority patent/JP2006519189A/ja
Priority to CA002514703A priority patent/CA2514703A1/fr
Priority to AU2004210416A priority patent/AU2004210416A1/en
Publication of WO2004069258A2 publication Critical patent/WO2004069258A2/fr
Publication of WO2004069258A3 publication Critical patent/WO2004069258A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/16—Ophthalmology
    • G01N2800/166—Cataract
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/16—Ophthalmology
    • G01N2800/168—Glaucoma

Definitions

  • the invention relates to the use of a functional inhibitor of the hsgkl or hsgk3 protein or a negative transcription regulator of the hsgkl or hsgk3 gene for the manufacture of a medicament for the therapy and / or prophylaxis of a cataract, glaucoma or diabetic neuropathy.
  • the invention relates to the use of a single- or double-stranded nucleic acid comprising the hsgkl sequence according to Acc No. NM_005627 or one of its fragments or comprising the hsgk3 sequence according to Acc. No. AF169035 or one of its fragments for diagnosing a predisposition to form cataract, glaucoma and / or diabetic neuropathy, and a kit for diagnosing a predisposition to form cataract, glaucoma and / or diabetic neuropathy, which comprises the above-mentioned nucleic acid.
  • Another object of the invention are various screening methods for the identification and characterization of therapeutically active substances from a large number of test substances for the therapy and / or prophylaxis of at least one disease selected from cataract, glaucoma and diabetic neuropathy.
  • the serum and glucocorticoid-inducible kinase hsgkl was originally cloned as a glucocorticoid-sensitive gene [Webster et al, Characterization of sgk, a novel member of the serine / threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 1993; 13: 2031-2040].
  • hsgkl is under the influence of a variety of stimuli [Lang F, Cohen P. Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Science STKE. 2001 Nov 13; 2001 (108): RE17], such as the mineralocorticoids [Chen et al, Epithelial sodium Channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sei USA 1999; 96: 2514-2519; Näray-Fejes-T ⁇ th et al, sgk is an aldosterone-induced kinase in the renal collecting duet. Effects on epithelial Na + channels.
  • sgk serum- and glucocorticoid-regulated kinase
  • the hsgkl is stimulated by the "insulin-like growth factor IGF1", by insulin and by oxidative stress via a signal cascade by phosphoinositol-3-kinase (PI3 kinase) and phosphoinositol-dependent kinase PDK1
  • PI3 kinase phosphoinositol-3-kinase
  • PDK1 phosphoinositol-dependent kinase
  • the hsgkl is a potent stimulator of the renal epithelial Na + channel [De la Rosa et al, The serum and glucocorticoid kinase sgk increases the abundance of epithelial sodium Channels in the plasma membrane of Xenopus oocytes. J Biol Chem 1999; 274: 37834-37839; Böhmer et al, The Shrinkage-activated Na + Conductance of Rat Hepatocytes and its Possible Correlation to rENaC. Cell Phys Biochem. 2000; 10: 187-194; Lang et al., Deranged transcriptional regulation of cell volume sensitive kinase hSGK in diabetic nephropathy.
  • the hsgkl and its human homologues should have considerable potential for the diagnosis of numerous diseases.
  • DE 197 08 173 AI shows in particular that the hsgkl for diagnosis in many diseases in which cell volume changes play a crucial pathophysiological role, such as hypernatremia, hyponatremia, diabetes mellitus, renal failure, hypercatabolism, hepatic encephalopathy and microbial or viral infections can be used.
  • WO 00/62781 has described that the hsgkl activates the endothelial Na + channel, which increases renal Na absorption. Since this increased renal Na absorption is associated with hypertension, it was assumed here that an increased expression of the hsgkl should lead to hypertension, a reduced expression of the hsgkl should ultimately lead to hypotension. -
  • DE 100 421 37 also describes a similar relationship between the overexpression or overactivity of the human homologues hsgk2 and hsgk3 with the overactivation of the ENaC, the resulting increased renal Na absorption and the hypertension that develops from this. Furthermore, the diagnostic potential of the kinases hsgk2 and hsgk3 regarding arterial hypertension has already been discussed.
  • WO02 / 074987 A2 the connection between the occurrence of two different polymorphisms (single nucleotide polymorphism (SNP)) of individual nucleotides in the hsgkl gene with a genetically determined predisposition to hypertension was disclosed. This is a polymorphism in intron 6 (T ⁇ C) and a polymorphism in exon 8 (C ⁇ T) in the hsgkl gene.
  • SNP single nucleotide polymorphism
  • nucleic acids containing polymorphic gene regions of the human homologues of the sgk family could be used to diagnose a predisposition for these further diseases . It was therefore an object of the invention to uncover further correlations between the function of the human homologs of the sgk family and new diseases and thus to provide new diagnostic uses for nucleic acids which contain polymorphic gene regions of the human homologues of the sgk family.
  • the glucose transporter Glutl provides, among other things, glucose uptake into different cells of the eye [Busik et al., Glucose-induced activation of glucose uptake in cells from the inner and outer blood-retinal barrier. luvest Ophthalmol Vis Be. 2002; 43: 2356-63; Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H. Ultracytochemical localization of the erythrocyte / HepG2- type glucose transporter (GLUT1) in the ciliary body and iris of the rat eye.
  • Glutl for the development of cataracts [Gong et al., Development of cataractous macrophthalmia in mice expressing an active MEK1 in the lens. Invest Ophthalmol Vis Sei. 2001; 42: 539-48].
  • Glutl overexpression requires the formation and deposition of connective tissue proteins £ Ayo et al., Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium. At the J Physiol.
  • the above-mentioned disorders would occur in all conditions in which the hsgkl has increased activity, that is to say in excess of all the above-mentioned hormones.
  • Certain polymorphisms of the hsgkl gene that correlate with increased blood pressure [Busjahn et al., Serum- and glucocorticoid-regulated kinase (SGK1) gene and blood pressure. Hypertension 40 (3): 256-260, 2002], could at the same time increase Lead to occurrence of cataract and glaucoma.
  • the same modifications of the gene should also correlate with premature cataract and / or glaucoma.
  • the present findings reveal a completely new mechanism in the regulation of the glucose transporter Glutl.
  • An increased activity of the hsgkl should therefore lead to an increased uptake of glucose in the cells.
  • the transcription of the hsgkl is carried out by serum [Webster et al. 1993], by glucocorticoids [Brenan & Corder 2000, Webster et al. 1993], by mineralocorticoids [Chen et al. 1999, Naray-Fejes-Toth et al. 1999, Shigaev et al.
  • FSH Follicle-Stimulating hormone
  • PKA protein kinase B
  • Sgk serum and glucocorticoid-induced kinase
  • the hsgkl transcription is increased by cell shrinkage, as the Waldegger et al. from 1997 shows.
  • An increased glucose concentration as occurs in diabetes mellitus, stimulates the expression of hsgkl by cell shrinkage and / or by increased formation of TGF-ß [Lang et al. 2000].
  • the expressed hsgkl is activated by the "insulin like growth factor" IGF1, by insulin and by oxidative stress [Kobayashi & Cohen 1999, Park et al. 1999, Kobayashi et al. 1999].
  • the increased expression of the hsgkl increases the activity of the glucose transporter Glut-1. This means that more glucose is absorbed into the cells and the water that follows through osmosis causes cell swelling. In this way, there is increased water retention in the cornea and lens, which leads to cataracts by reducing transparency [Gong et al. 2001]. Glaucoma could also develop in a similar way and additionally through the incorporation of connective tissue [Fingert et al. 2001].
  • hsgkl plays a role in this mechanism and is therefore suitable as a target protein for the diagnosis and therapy of glaucoma.
  • One object of the invention thus relates to the use of a functional inhibitor of the hsgkl or hsgk3 protein or a negative transcription regulator of the hsgkl or hsgk3 gene to reduce cell swelling.
  • Another object of the invention relates to the use of a 'functional inhibitor of the hsgkl or hsgk3 protein or a negative transcription regulator of the hsgkl or hsgk3 gene for the production of a medicament for the therapy and / or prophylaxis of a cataract, a glaucoma or the diabetic neuropathy.
  • This functional inhibitor of the hsgkl protein or the hsgk3 protein can be a chemical substance of any kind which inhibits the normal physiological activity of the hsgkl protein or the hsgk3 protein.
  • the functional inhibitor of the hsgkl or hsgk3 protein is preferably a low-molecular chemical substance (a "small molecule") or a protein or peptide.
  • the functional inhibitor of the hsgkl protein or the hsgk3 protein can in particular be an antagonist of these enzymes, which blocks the substrate binding site of the hsgkl protein or the hsgk3 protein, but at the same time, no catalytic conversion is accessible through the hsgkl or hsgk3.
  • suitable antagonists are preferably those molecules which have structural similarity to the natural substrate of the hsgkl protein or the hsgk3 protein, that is to say in particular a structural similarity to the phosphorylatable amino acids serine and threonine.
  • Staurosporin and chele-rythrin are two known functional inhibitors of hsgkl.
  • either staurosporin or chelerythrine is therefore used as the functional inhibitor of the hsgkl or the hsgk3 for the therapy and / or prophylaxis of at least one of the diseases cataract, glaucoma or diabetic neuropathy.
  • a negative transcription regulator of the hsgkl gene or the hsgk3 gene is defined as a substance which activates the expression of the hsgkl gene or the hsgk3 gene at the transcription level.
  • the medicament according to the invention for the therapy and / or prophylaxis of a cataract, glaucoma or diabetic neuropathy can, in addition to the actual active substance, the functional inhibitor or the negative transcription regulator of the hsgkl or the hsgk3, additionally stabilizers and / or carrier substances, such as starch, lactose , Stearic acid, fats, waxes, alcohols or other additives such as preservatives, colors or flavors.
  • the drug can be administered in any way, in particular orally, in the form of tablets, granules, capsules or as a solution.
  • Other particularly suitable dosage forms relate to direct applications (e.g. on the skin or eye) in the form of ointments, tinctures, sprays or any type of injection (e.g. subcutaneous, intravenous) or infusion.
  • Another object of the invention is the use of a single or double-stranded nucleic acid comprising the hsgkl sequence according to Acc No. NM_005627 or one of its fragments to diagnose a predisposition to develop cataracts, glaucoma and / or diabetic neuropathy.
  • the fragment of hsgkl, which the single or double-stranded nucleic acid can comprise is at least 10 nucleotides / base pairs long, preferably at least 15 nucleotides / base pairs long and in particular at least 20 nucleotides / base pairs long.
  • the single- or double-stranded nucleic acid here preferably comprises at least one polymorphic nucleotide of the hsgkl gene, in particular a “single nucleotide polymorphism (SNP)” of the hsgkl gene.
  • the single- or double-stranded nucleic acid comprises at least one of the following SNPs of the hsgkl gene: a G insertion at position 732/733 in intron 2 of the hsgkl gene,
  • the above SNPs of the hsgkl gene in the patient's genomic DNA or cDNA can preferably be detected using the abovementioned single or double-stranded nucleic acids by the following methods: by direct sequencing of the genomic DNA or cDNA with the above nucleic acids, by specific hybridization the genomic DNA or cDNA with the above nucleic acids, by a PCR oligonucleotide elongation assay or by a ligation assay.
  • the patient's genomic DNA or cDNA is preferably isolated from a patient's body sample, in particular from saliva, blood, tissue or cells.
  • the activity of the expressed hsgkl gene depends on the version of this polymorphism in the patient's hsgkl gene and that nucleic acids which contain at least one of these polymorphisms are therefore particularly good for diagnosing a predisposition to the development of cataracts, glaucoma and / or diabetic neuropathy.
  • the invention further relates to the use of a single- or double-stranded nucleic acid comprising the hsgk3 sequence according to Acc No. AF169035 or one of its fragments to diagnose a predisposition to develop cataract, glaucoma and / or diabetic neuropathy.
  • the fragment of hsgk3, which the single or double-stranded nucleic acid can comprise, is at least 10 nucleotides / base pairs long, preferably at least 15 nucleotides / base pairs long and in particular at least 20 nucleotides / base pairs long.
  • the single- or double-stranded nucleic acid preferably comprises at least one polymorphic nucleotide of the hsgk3 gene, in particular a “single nucleotide polymorphism (SNP)” of the hsgk3 gene.
  • SNP single nucleotide polymorphism
  • certain antibodies which are directed against substrates of the human homologues of the sgk family, in particular against substrates of the hsgkl and hsgk3 are also suitable for diagnosing a predisposition to the formation of at least one of the diseases cataract, Glaucoma, diabetic neuropathy.
  • diagnostic antibodies are preferably directed against such an epitope of the human homologues of the sgk family (in particular the hsgkl and the hsgk3) which contains the phosphorylation site of the substrate either in phosphorylated form or in nonphosphorylated form.
  • an overexpression of the hsgkl protein that occurs due to the individual genetic makeup of the hsgkl gene could lead to an increased implementation of
  • Hsgk substrates i.e. to an increased enzymatic phosphorylation of the
  • Glutl glucose transporter
  • the ubiquitin protein ligase Nedd4-2 (Acc No. BAA23711) is used as the substrate of the human homologue of the sgk family.
  • This ubiquitin protein ligase is a protein which is specifically phosphorylated by the human homologues of the sgk family [Debonneville et al., Phosphorylation of Nedd4-2 by Sgkl regulates epithelial Na (+) channel cell surface expression. EMBO J., 2001; 20: 7052-7059; Snyder et al., Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na (+) channel. J. Biol.
  • Phosphorylation sites for the hsgkl have the consensus sequence (R X R X X S / T), where R is arginine, S is serine, T is threonine and X is any amino acid.
  • R is arginine
  • S is serine
  • T is threonine
  • X is any amino acid.
  • Nedd4-2 2 Acc No. BAA23711
  • the abovementioned antibodies for diagnosing a predisposition to develop at least one of the diseases cataract, glaucoma, diabetic neuropathy are therefore preferably directed against the substrate Nedd4-2 and particularly preferably against directed a protein region of Nedd4-2 with the sequence of the potential phosphorylation site for the hsgkl, the consensus sequence (RXRXXS / T).
  • these antibodies are directed against those Nedd4-2 protein regions which comprise at least one of the two potential phosphorylation sites serine at amino acid position 382 and / or serine at amino acid position 468.
  • kits for the diagnosis of one of the diseases cataract, glaucoma and diabetic neuropathy comprising at least one of the following components: " - Antibodies which are directed against hsgkl or hsgk3, single or double-stranded nucleic acids which with the hsgkl - Gene according to Acc No. NM_005627 or with the hsgk3 gene according to Acc No. AF169035 can hybridize under stringent conditions; in particular those single- or double-stranded nucleic acids which comprise polymorphic nucleotides, in particular “SNPs” of the hsgkl gene or the hsgk3 gene,
  • Antibodies directed against a substrate of a human homologue of the sgk family preferably antibodies directed against the phosphorylation site of this substrate in the phosphorylated or non-phosphorylated form; especially antibodies directed against the phosphorylation site of Nedd4 or Nedd4-2 in the phosphorylated or non-phosphorylated form.
  • the invention further relates to a screening method for identifying and characterizing therapeutically active substances from a large number of test substances for therapy and / or prophylaxis of at least one disease selected from the group consisting of cataract, glaucoma and diabetic neuropathy, comprising the following steps: a) heterologous coexpression of i) the glucose transporter Glutl and ii) the hsgkl and / or the hsgk3 in cells, b) cultivation of at least one cell portion Ai to A in the presence of at least one test substance, wherein the at least one test substance differs depending on the index 1 to X of the Zeil portion and Cultivation of a control cell part B in the absence of any test substance, c) determination of the activity of the glucose transporter Glutl in the Zeil fractions Ai to Ax compared to the activity of the glucose transporter Glutl in the control cell part B.
  • suitable cells preferably mammalian cells or cell lines, in particular human cells or cell lines with suitable expression vectors, contain suitable expression cassettes for the expression of Glutl and of hsgkl and / or hsgk3 according to standard methods, such as electroporation, CaPO4 precipitation, lipofection or the like, transfected.
  • the expression cassettes contain the genomic DNA or the cDNA of the target gene in question (Glutl, hsgkl, hsgk3) under the control of suitable promoters which are active in the cell type in question and can express the target gene in a suitable amount.
  • the expression vectors can also contain selection markers.
  • the transfected cells are then cultivated under conditions which allow expression of the target genes i) and ii).
  • step b) the transfected cells from a) are divided into different Zeil parts (aliquots) Ai to Ax and a control cell part B.
  • the Zeil parts Ai to Ax are each in the presence of at least one test Cultivated substance.
  • the test substance (s) added to the Zeil fractions Ai to Ax differ from one another (depending on the index 1 to X of the respective Zeil fractions A ⁇ to Ax).
  • the control cell portion B is cultivated in the absence of any test substance.
  • step c) the activity of the glucose transporter Glutl in the Zeil fractions Ai to Ax is quantitatively determined in comparison to the activity of the glucose transporter Glutl in the control cell fraction B.
  • a test substance that can functionally inhibit the hsgkl or the hsgk3 should have been added to the Zeil portions Ai to Ax, in which a significantly lower value of the Glutl activity is measured compared to the control Zeil portion B. or reduces their expression.
  • Such a substance could be suitable for the therapy of at least one of the diseases cataract, glaucoma or diabetic neuropathy.
  • Fig. 1 The invention is illustrated by the following Fig. 1.
  • the ordinate A in Fig. 1 shows the uptake of 2-deoxyglucose (in pmol 1/10 min / oocyte) (arithmetic mean ⁇ SEM).
  • Xenopus laevis oocytes were injected with cRNA from Glut-1 with or without cRNA from SGK1, SGK2, SGK3 or protein kinase B (PKB) (see Example 1).
  • PKA protein kinase B
  • Fig. 1 shows the increased uptake of 2-deoxyglucose in those oocytes which, in addition to glut 1, express the hsgkl or the hsgk3 in comparison to those oocytes which express glut 1 alone. This shows that the function of the hsgkl and the hsgk3 efficiently stimulate the activity of the glucose transporter Glutl. A similar effect is not found for those oocytes which express the hsgk2 or PKBmut instead of hsgkl or hsgk3.
  • the invention is illustrated by the following example.
  • Example 1 Expression in Xenopus laevis oocytes and two-electrode voltage clamp cRNA of normal SGKl [Waldegger S, Barth P, Raber G, Lang F: Cloning and characterization of a putative human serine / threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume.
  • Xenopus laevis ovaries The dissection of Xenopus laevis ovaries and the collection and treatment of oocytes have already been described in detail [Wagner CA, Friedrich B, Setiawan I, Lang F, Bröer S: The use of Xenopus laevis ooeytes for the functional characterization of heterologously expressed membrane proteins. Cell Physiol Biochem 2000; 10: 1-12].
  • the oocytes were injected with 5 ng of human glutl, 7.5 ng of human SGKl and / or with 5 ng of Xenopus Nedd4-2. ControUocytes were injected with water. The uptake of radioactively labeled glucose was measured at room temperature 2 days after injection of the respective cRNAs.
  • the control bath solution contained 96 mM NaCl, 2 mM KC1, 1.8 mM CaCl 2 , 1 mM MgCl 2 and 5 mM HEPES, pH 7.4. All substances were used in the specified concentrations. The final solutions were nitrated to pH 7.4 with HC1 or NaOH.
  • n is the number of oocytes examined. All experiments were carried out in at least three different groups of oocytes. The results were tested for significant differences using the Student t-test. Only results with P ⁇ 0.05 were considered to be statistically significant.

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Abstract

La présente invention concerne l'utilisation d'un inhibiteur fonctionnel de la protéine hsgk1 ou hsgk3 ou d'un régulateur de transcription négatif du gène hsgk1 ou hsgk3, pour la préparation d'un produit pharmaceutique qui sert à traiter et/ou à prévenir la cataracte, le glaucome ou la neuropathie diabétique. Un autre aspect de l'invention concerne l'utilisation d'un acide nucléique double ou simple brin comprenant la séquence hsgk1 selon Acc No. NM_005627 ou un fragment de celui-ci, ou comprenant la séquence hsgk3 selon Acc. No. AF169035 ou un fragment de celui-ci, pour diagnostiquer une prédisposition à l'apparition d'une cataracte, d'un glaucome et/ou d'une neuropathie diabétique, ainsi qu'un kit pour diagnostiquer une prédisposition à l'apparition d'une cataracte, d'un glaucome et/ou d'une neuropathie diabétique, ledit kit comprenant l'acide nucléique mentionné ci-dessus. L'invention a également pour objet différents procédés de criblage pour identifier et caractériser des substances à action thérapeutique, à partir d'une pluralité de substances d'essai, afin de traiter et/ou de prévenir au moins l'une des maladies que son la cataracte, le glaucome et la neuropathie diabétique.
PCT/EP2004/001048 2003-02-07 2004-02-05 Utilisation de la famille genique sgk pour diagnostiquer et pour traiter la cataracte et le glaucome WO2004069258A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP04708350A EP1663246A2 (fr) 2003-02-07 2004-02-05 Utilisation de la famille genique sgk pour diagnostiquer et pour traiter la cataracte et le glaucome
MXPA05008394A MXPA05008394A (es) 2003-02-07 2004-02-05 Uso de la familia de genes sgk para el diagnostico y terapia de cataratas y glaucoma.
BR0407300-2A BRPI0407300A (pt) 2003-02-07 2004-02-05 Usos de um inibidor funcional da proteìna hsgk1 ou da proteìna hsgk3 ou de um regulador negativo da transcrição do gene hsgk1 ou do gene hsgk3, de um ácido nucleico de filamento único ou filamento duplo e de um anticorpo, fármaco, kit para diagnóstico, e, método de triagem para identificar e caracterizar substâncias terapeuticamente ativas
JP2006501737A JP2006519189A (ja) 2003-02-07 2004-02-05 白内障および緑内障を診断および治療するための、ｓｇｋ遺伝子ファミリーの使用
CA002514703A CA2514703A1 (fr) 2003-02-07 2004-02-05 Utilisation de la famille genique sgk pour diagnostiquer et pour traiter la cataracte et le glaucome
AU2004210416A AU2004210416A1 (en) 2003-02-07 2004-02-05 Use of the sgk gene family for diagnosis and therapy of cataracts and glaucoma

Applications Claiming Priority (2)

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DE10305212A DE10305212A1 (de) 2003-02-07 2003-02-07 Verwendung der sgk-Genfamilie zur Diagnose und zur Therapie von Katarakt und Glaukom
DE10305212.7 2003-02-07

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WO2004069258A2 true WO2004069258A2 (fr) 2004-08-19
WO2004069258A3 WO2004069258A3 (fr) 2005-02-24

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JP (1) JP2006519189A (fr)
KR (1) KR20050114214A (fr)
CN (1) CN1771039A (fr)
AU (1) AU2004210416A1 (fr)
BR (1) BRPI0407300A (fr)
CA (1) CA2514703A1 (fr)
DE (1) DE10305212A1 (fr)
MX (1) MXPA05008394A (fr)
PL (1) PL378399A1 (fr)
RU (1) RU2005127808A (fr)
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WO2005094796A2 (fr) * 2004-03-11 2005-10-13 Merck Patent Gmbh Methodes d'interference avec la fibrose
WO2005094829A1 (fr) * 2004-03-11 2005-10-13 Merck Patent Gmbh Modulation du glutamate pour le traitement de troubles neuropsychiatriques m, avec utilisation de modulateurs de kinases inductibles par serum et glucocorticoide
WO2006061130A2 (fr) * 2004-12-10 2006-06-15 Sanofi-Aventis Deutschland Gmbh Utilisation d'une kinase activee par le serum et les glucocorticoides
WO2007002670A2 (fr) * 2005-06-28 2007-01-04 Bausch & Lomb Incorporated Procede pour faire baisser la pression intraoculaire
WO2007037560A1 (fr) * 2005-09-30 2007-04-05 Link Genomics, Inc. Application therapeutique ou diagnostique du gene sgk2
WO2008079980A1 (fr) * 2006-12-22 2008-07-03 Alcon Research, Ltd. Inhibiteurs de la protéine kinase c-delta pour le traitement du glaucome
CN101360999B (zh) * 2005-11-22 2013-07-17 麦吉尔大学 眼内压调节早期基因及其用途

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DE102008029072A1 (de) * 2008-06-10 2009-12-17 Lang, Florian, Prof. Dr.med. Sgk3 als therapeutisches und diagnostisches Target für Alterserkrankungen
BR112013018374A2 (pt) * 2011-01-25 2016-10-11 Monell Chemical Senses Centre composições e métodos para fornecer ou modular o sabor doce e métodos para rastrear os mesmos
KR102357260B1 (ko) * 2020-12-10 2022-02-08 주식회사 레피겐엠디 마이크로rna를 이용한 당뇨병성 신경병증의 예측 및 진단 방법 및 이를 위한 키트

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005094796A2 (fr) * 2004-03-11 2005-10-13 Merck Patent Gmbh Methodes d'interference avec la fibrose
WO2005094829A1 (fr) * 2004-03-11 2005-10-13 Merck Patent Gmbh Modulation du glutamate pour le traitement de troubles neuropsychiatriques m, avec utilisation de modulateurs de kinases inductibles par serum et glucocorticoide
WO2005094796A3 (fr) * 2004-03-11 2006-12-28 Merck Patent Gmbh Methodes d'interference avec la fibrose
WO2006061130A2 (fr) * 2004-12-10 2006-06-15 Sanofi-Aventis Deutschland Gmbh Utilisation d'une kinase activee par le serum et les glucocorticoides
WO2006061130A3 (fr) * 2004-12-10 2007-04-26 Sanofi Aventis Deutschland Utilisation d'une kinase activee par le serum et les glucocorticoides
WO2007002670A2 (fr) * 2005-06-28 2007-01-04 Bausch & Lomb Incorporated Procede pour faire baisser la pression intraoculaire
WO2007002670A3 (fr) * 2005-06-28 2007-04-05 Bausch & Lomb Procede pour faire baisser la pression intraoculaire
WO2007037560A1 (fr) * 2005-09-30 2007-04-05 Link Genomics, Inc. Application therapeutique ou diagnostique du gene sgk2
CN101360999B (zh) * 2005-11-22 2013-07-17 麦吉尔大学 眼内压调节早期基因及其用途
WO2008079980A1 (fr) * 2006-12-22 2008-07-03 Alcon Research, Ltd. Inhibiteurs de la protéine kinase c-delta pour le traitement du glaucome

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MXPA05008394A (es) 2005-10-05
CN1771039A (zh) 2006-05-10
EP1663246A2 (fr) 2006-06-07
CA2514703A1 (fr) 2004-08-19
RU2005127808A (ru) 2006-05-27
KR20050114214A (ko) 2005-12-05
JP2006519189A (ja) 2006-08-24
WO2004069258A3 (fr) 2005-02-24
DE10305212A1 (de) 2004-08-19
BRPI0407300A (pt) 2006-02-07
ZA200506280B (en) 2006-05-31
PL378399A1 (pl) 2006-04-03
AU2004210416A1 (en) 2004-08-19

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