EP1317265A2 - Procede pour diagnostiquer des maladies neuronales et pour traiter l'hemostase primaire deficiente - Google Patents

Procede pour diagnostiquer des maladies neuronales et pour traiter l'hemostase primaire deficiente

Info

Publication number
EP1317265A2
EP1317265A2 EP01971618A EP01971618A EP1317265A2 EP 1317265 A2 EP1317265 A2 EP 1317265A2 EP 01971618 A EP01971618 A EP 01971618A EP 01971618 A EP01971618 A EP 01971618A EP 1317265 A2 EP1317265 A2 EP 1317265A2
Authority
EP
European Patent Office
Prior art keywords
serotonin
tph
treatment
production
reduced
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP01971618A
Other languages
German (de)
English (en)
Inventor
Diego Walther
Michael Bader
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Original Assignee
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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 Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft filed Critical Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Publication of EP1317265A2 publication Critical patent/EP1317265A2/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • 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
    • 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
    • A61K31/436—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 six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to a method for the diagnosis of neuronal diseases and for the treatment of deficient primary hamostasis. Furthermore, the invention relates to a method for suppressing the immune system, which u. a. is important for transplantation medicine and for the treatment of allergies. Areas of application of the invention are medicine and the pharmaceutical industry.
  • serotonin is a neurotransmitter u. a. to stimulate peristalsis, vasodilation or constriction (dose-dependent) and increase muscle tone in the respiratory tract. It is not only a neurotransmitter in the CNS, but also a compound found everywhere in the periphery, where serotonin was first discovered through its activity as a strong vasoconstrictor (Ra ⁇ port et al., J. Biol. Chem. 176: 1237, 1948).
  • serotonin plays a crucial role in primary hamostasis, i.e. the hemostasis.
  • the serotonin stored in platelets is released at vascular lesion sites, after which it interferes with the primary hamostasis (Holland, Proc. Soc. Exp. Biol. Med. 151: 32-39, 1976).
  • TPH tryptophan hydroxylase
  • the invention is therefore based on the object of improving the diagnosis of neuronal diseases of the type mentioned. Another task is to develop means for the treatment of deficient primary hamostasis and means for suppression of the immune system based on new knowledge of the effect of serotonin,
  • the invention is implemented according to the claims.
  • the invention is based on the essential discovery that serotonin is synthesized in the body by differently expressed TPH isoenzymes in the neurons and in peripheral tissues. Genetic targeting has shown that an isoform, the peripheral enzyme (also called TPH), is responsible for maintaining primary hamostasis and T-cell mediated immune responses. Another isoform, the newly identified neuron-specific TPH (called nTPH) synthesizes serotonin independently in the CNS. Furthermore, some mechanisms have been elucidated. It was found a) that the main step of serotonin in primary hamostasis is mediated by von Willebrand factor. Furthermore, it was found that b) the serotonin in the blood platelets is essential for the normal number of circulating CD4 + cells and for their normal activity and thus represents a new target for immunosuppressive treatment.
  • TPH peripheral enzyme
  • nTPH neuron-specific TPH
  • the invention primarily relates to inhibitors or promoters of the two TPH isoforms which can be used for the diagnosis of neuronal diseases and for the treatment of deficient primary hamostasis. Furthermore, the invention relates to the use of these inhibitors for suppression of the immune system, which u. a. is important for transplantation medicine and for the treatment of allergies.
  • the method is characterized by influencing the nTPH and / or TPH regulation and thus the targeted serotonin production in the body.
  • the peripheral TPH has been shown to be necessary for primary hamostasis and for the T cell mediated immune response, whereas the newly identified nTPH, which is independently expressed and synthesizes serotonin in the CNS, is responsible for the serotonergic effects in behavioral physiology. This opens up new pharmacological possibilities for immunosuppression and for therapeutic influencing of hamostasis.
  • the nTPH and / or TPH regulation is influenced in the following ways: Specific inhibitors of the peripheral TPH isoforms are developed, which are based on the molecular differences described in the TPH isoforms, and on the other hand also inhibitors which are not common in the blood-brain barrier are. Specific inhibitors for the TPH isoforms can be found in vitro using very simple standard screening methods, since the cDNAs obtained from the two isoforms can be used with the aid of expression systems for the targeted expression of the pure isoforms. In addition to the diagnostic benefit, these inhibitors also have therapeutic applications, because elevated serotonin levels in the blood are found in a variety of complications.
  • a side effect of antidepressants that block the serotonin transporter is the occurrence of acute bleeding episodes, apparently due to insufficient serotonin storage in the platelets of the treated Patients.
  • the platelet serotonin transporter is identical to the actual target of the antidepressants, the CNS serotonin transporter.
  • the antidepressants are usually discontinued, with the result that the patient's condition deteriorates and the risk of depression-related suicide increases. This does not have to happen if commercial Willebrand factor (vWF) is infused in such an acute bleeding episode.
  • vWF commercial Willebrand factor
  • CsA cyclosporin A
  • the immunosuppressive effect of reduced serotonin levels in the blood can be used to apply the toxic substances, CsA, FK506 and rapamycin in lower doses.
  • the nTPH and / or TPH regulation can be influenced in the following ways:
  • nTPH and / or pTPH takes place molecular-biologically with ribozymes, antisense oligonucleotides or by antisense RNA expression, the sequence differences of the isoform mRNAs permitting only one mRNA to be influenced in each case.
  • pharmacological approaches with the help of specific TPH inhibitors, such as. B. p-chlorophenylalanine or p-ethynylphenylalanine worked.
  • Serotonin production is stimulated from a molecular biological point of view by tissue-specific overexpression of the TPH isoforms; pharmacologically, for example, the predecessor substance, 5-hydroxytryptophan, or substituted analogues can be administered, but not least also serotonin itself.
  • the method according to the invention for the diagnosis of neuronal diseases is characterized in that a specific inhibition of peripheral serotonin biosynthesis is carried out, subsequently the metabolite concentrations originating from the CNS are determined and the degree of disease is determined on the basis of a comparison curve. To do this, it is necessary to use substances that are not blood-brain barriers.
  • the invention also relates to the newly found neuronal tryptophan hydroxylase (nTPH), which differs from the previously known TPH in the regulatory domain (the catalytic domain is identical).
  • nTPH has the amino acid sequence given in Fig. 9.
  • A Schematic representation of the targeting process. The first four of the 11 exons of the TPH gene are indicated.
  • the knockout construct was integrated into an allele of ES cells by homologous recombination, thereby inactivating the first coding exon of the TPH gene.
  • the integrated neomycin resistance cassette also contains a transcription stop sequence.
  • the positions of the analytical amplicons for wild type and knockout identification are given, as well as the positions of the internal and external Southern blot probes.
  • the Eco Rl sites that enable the identification of wild-type and knockout animals in Southern blots are highlighted in bold (RI). Restriction sites: RI: Eco RI; Hd: Hind III; Bm: Bam HI; Sc: Sac I.
  • Trp and 5-HT in whole blood and in duodenum samples from 129SvJ, C57BL / 6, TPH (- / -), and TPH (+ / +) mice. Nd: undetectable ( ⁇ 25 fg / ⁇ l). *: statistically significant compared to all other mouse lines (p ⁇ 0.05).
  • 5-HT is significantly reduced in the hippocampus of TPH (- / -) mice compared to TPH (+ / +) mice, but not compared to the other laboratory mouse lines.
  • TPH (- / -) mice Prolonged bleeding times of TPH (- / -) animals. Normal bleeding times from control animals are 8-11 min, whereas TPH (- / -) mice bleed for an average of 35 min.
  • FIG. 1 Exemplary view of rejection of secondary skin grafts.
  • Arrowheads mark the sensitizing first grafts, arrows the second grafts.
  • the grafts on TPH (+ / +) and C57BL / 6 animals are noticeable at the same time after the transplant due to lack of revascularization and inflammation at the wound edges (white rejection) , or have already been completely rejected (first graft and two of the second grafts on the C57BL / 6 tier).
  • the ORF is highlighted in bold in the trinucleotide notation. In the 5 'flanking area, part of the putative new promoter is shown, in which a TATA box and the most probable transcription start point (+1) are marked.
  • the splicing donor site of exon 2b is shown in the 3 'flanking region. Intron sequences were highlighted in lower case, with the short intron of 53 bp symbolically spanned by a line from the sections of the ORF. For the sake of clarity, the respective consensus sequences were given under the splicing donor sites, branching site and acceptor site involved.
  • variant A is the known form of the TPH-n RNA.
  • Variant A has already been cloned and encodes an active TPH isoform.
  • Variants C and C lead to the expression of only the regulatory domains. To simplify matters, the mRNAs are only shown up to the 6th exon out of the 11 exons.
  • the upper part of the sequences shows the new section of TPH.
  • the conserved sequence sections of the regulatory domains of the AAAHs are given below.
  • the sequences were compared individually using the ClustalW program, and then put together by hand. Larger gaps were sometimes allowed to highlight the matching structural elements.
  • Striking sequence motifs are framed and named individually. Four of the five motifs match elements of the PAH secondary structure. Partially overlapping with the IEDN motif, an area of the regulatory domain is framed and highlighted in gray, which extends into the furrow of the catalytic center, as is known from crystallographic studies by PAH. Further explanations in the text.
  • nstph neuron-specific TPH (the new variant) of the mouse
  • musth TH of the mouse
  • muspah and humpah murine and human PAH
  • ptph peripheral TPH of the mouse (known variant).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Pathology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé pour diagnostiquer des maladies neuronales et pour traiter l'hémostase primaire déficiente. Elle concerne en outre un procédé permettant de réduire l'activité du système immunitaire, ce qui est important, entre autres, pour la médecine de transplantation et pour le traitement des allergies. Les domaines d'application de cette invention sont la médecine et l'industrie pharmaceutique. L'invention est réalisée conformément aux revendications. L'invention est fondée sur la découverte essentielle selon laquelle la sérotonine est synthétisée dans le corps par des iso-enzymes TPH exprimées de façon différente dans les neurones et dans les tissus périphériques. Il a été prouvé, par ciblage génique, qu'une isoforme, l'enzyme périphérique (dénommée ci-après TPH), est responsable du maintien de l'hémostase primaire et des réponses immunitaires induites par les cellules T. Une autre isoforme, la TPH spécifique des neurones, nouvellement identifiée (appelée nTPH) synthétise la sérotonine, de façon indépendante par rapport à la première isoforme, dans le système nerveux central. L'invention concerne également la nouvelle triptophane hydroxylase neuronale (nTPH) découverte, laquelle se différencie des TPH connus, dans les domaines régulatoires.
EP01971618A 2000-08-31 2001-08-27 Procede pour diagnostiquer des maladies neuronales et pour traiter l'hemostase primaire deficiente Ceased EP1317265A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10043124A DE10043124A1 (de) 2000-08-31 2000-08-31 Verfahren zur Diagnostik von neuronalen Erkrankungen sowie zur Behandlung der defizienten primären Hämostase
DE10043124 2000-08-31
PCT/DE2001/003178 WO2002017891A2 (fr) 2000-08-31 2001-08-27 Procede pour diagnostiquer des maladies neuronales et pour traiter l'hemostase primaire deficiente

Publications (1)

Publication Number Publication Date
EP1317265A2 true EP1317265A2 (fr) 2003-06-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP01971618A Ceased EP1317265A2 (fr) 2000-08-31 2001-08-27 Procede pour diagnostiquer des maladies neuronales et pour traiter l'hemostase primaire deficiente

Country Status (5)

Country Link
US (1) US7049336B2 (fr)
EP (1) EP1317265A2 (fr)
JP (1) JP2004507491A (fr)
DE (1) DE10043124A1 (fr)
WO (1) WO2002017891A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10232151A1 (de) * 2002-07-16 2004-02-05 Max-Delbrück-Centrum für Molekulare Medizin Neuronal exprimierte Tryptophanhydroxylase und ihre Verwendung
WO2005041750A2 (fr) * 2003-10-24 2005-05-12 Merck & Co., Inc. Procede d'identification de composes qui affectent l'expression de tryptophane hydroxylase de l'isoforme 2
US8093291B2 (en) * 2007-06-26 2012-01-10 Lexicon Pharmaceuticals, Inc. Methods of using and compositions comprising tryptophan hydroxylase inhibitors
US11197916B2 (en) 2007-12-28 2021-12-14 Takeda Pharmaceutical Company Limited Lyophilized recombinant VWF formulations
KR101643277B1 (ko) * 2007-12-28 2016-07-28 박스알타 인코퍼레이티드 재조합 ｖｗｆ 제제
CA2740919A1 (fr) * 2008-10-21 2010-04-29 Baxter International Inc. Formulations de vwf recombinant lyophilise
RU2012131290A (ru) * 2009-12-21 2014-01-27 Юниверсити Колледж Корк, Нэшнл Юниверсити Оф Айеленд, Корк Выявление риска возникновения преэклампсии

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3686414A (en) 1969-03-06 1972-08-22 Billie Kenneth Koe P-chlorobenzyl compounds and their serotonin lowering ability
AU8770282A (en) 1981-08-27 1983-03-03 Shaun R. Coughlin Composition for the treatment of atherosclerosis
DE3686622T2 (de) 1985-09-11 1993-04-01 British Tech Group Verwendung von dioxopiperidin-derivaten zur behandlung von anxietas, zur herabsetzung von chronischen abnormal hohen gehirn-spiegeln serotonins oder 5-hydroxy-indolessigsaeure und zur behandlung von bakteriellen oder viralen infektionen.
DE10112882A1 (de) * 2001-03-15 2002-09-19 Max Delbrueck Centrum Verwendung von Tryptophan-Derivaten zur spezifischen zytostatischen Behandlung von Serotonin-produzierenden Tumoren

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0217891A3 *

Also Published As

Publication number Publication date
JP2004507491A (ja) 2004-03-11
US20040014656A1 (en) 2004-01-22
WO2002017891A2 (fr) 2002-03-07
WO2002017891A3 (fr) 2002-10-17
DE10043124A1 (de) 2002-03-14
US7049336B2 (en) 2006-05-23

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