WO2012139732A1 - Préparation contenant disc1 et/ou au moins un fragment de disc1 à utiliser pour le traitement thérapeutique du corps humain ou animal - Google Patents

Préparation contenant disc1 et/ou au moins un fragment de disc1 à utiliser pour le traitement thérapeutique du corps humain ou animal Download PDF

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WO2012139732A1
WO2012139732A1 PCT/EP2012/001511 EP2012001511W WO2012139732A1 WO 2012139732 A1 WO2012139732 A1 WO 2012139732A1 EP 2012001511 W EP2012001511 W EP 2012001511W WO 2012139732 A1 WO2012139732 A1 WO 2012139732A1
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disc1
preparation according
treatment
fragment
rats
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English (en)
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Carsten Korth
Joseph P. HUSTON
Martin PUM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a novel preparation for use in the therapeutic treatment of the human or animal body, in particular for the modulation of neurochemical processes and behavior, wherein in one embodiment the preparation has at least one DISC fragment in combination with an immunostimulating substance.
  • the DISC1 protein is thought to play a key role in genetic engineering studies (Chubb et al., 2008, Molecular Psychiatry 13:36) and reverse genetic studies on animal models (Shen et al., 2008, J. Neuroscience 48: 10893) Attributed to control of behavioral control and mental homeostasis. Inter alia, animals that modeled dysfunctionality of DISCI also had learning or memory disorders as well as disorders of sensory gating or depression-like symptoms (reviewed in Shen et al., 2008, J. Neuroscience 48: 10893).
  • DISCl is a protein whose function is not yet conclusively known. It plays a role in neuronal development both in the proliferation of neuronal progenitor cells and in neuronal differentiation, neuronal migration and the formation of a functional dopamine metabolism (Niwa et al., 2010, Neuw. ron 65: 480).
  • DISC1 is a cytosolic-expressed protein lacking typical signal sequences that allow export to the endoplasmic reticulum. In this respect, according to the state of the art, it is not to be expected that it will be present extracellularly in biologically-functionally relevant quantities and that it can be used as a target occurring outside the cell, for example.
  • WO 2009/154697 describes a method for the treatment of neurological disorders in which a DISCl activator is administered.
  • the activator may be e.g. to act DISCl.
  • no distinction is made between monomeric and multimeric DISC, which both activate differently, eg. with antagonistic effects.
  • immunogenic effects, in particular of multimeric DISC are not discussed.
  • DISCI fragments are designated in the publication with numbers indicating the position of the first and last amino acid of the fragment in the sequence of the DISC1 protein. This designation of DISCI fragments is also used in the present application.
  • the object of the invention is to provide new applications for DISC1 or DISC1 fragments.
  • a preparation containing DISC1 and / or at least one DISC1 fragment as a therapeutic for the treatment or modulation of neurochemical processes in the human or animal body or for influencing the proliferation or migration of cells.
  • a multimeric DISC1 fragment is used.
  • Open-field tests are animal experiments in which test animals are placed in open-top, mostly bright containers, usually with a footprint of 1 meter x 1 meter. During the experiment the conditions (lighting, temperature etc.) are kept constant. After a rat or a test animal is placed in the container, the location changes of the animal over a certain period of time observed and quantified. The tests are based on the fact that animals want to avoid the stay on an unknown, brightly lit open space as far as possible. If they are nevertheless brought into such an environment, they show a movement behavior that is dictated by timidity, readiness to flee and curiosity.
  • ABM-ZK consists of 0.5 mg trehalose dimycolate (TDM), 0.5 mg monophosphoryl lipid A (MPL), 0.5 mg Cell Wall Skeleton (CWS), 2% oil (squalene) and an unspecified amount of Tween 80th
  • DISC1 fragments e.g. DISCI 765-854, 598-854, DISCI 1-854, or fragments other than those mentioned in the above-cited publication have a similar effect. It is conceivable to use as a single protein or peptide or as a fusion protein.
  • Amphetamine sensitizations are used in animal studies to elicit neurochemical balance disorders similar to those in neuropsychiatric disorders with schizophrenia-typical symptoms.
  • DISC1 fragments may induce immunogenic and / or psychotropic effects, both of which are e.g. cause a modulation of anxiety behavior.
  • the ratios of rats can be transferred to humans, so that it is readily conceivable, for example drugs prepared from DISCI fragments as tranquilizers or for the therapy of neuropsychiatric disorders, in particular those disorders which interfere with the DISCI metabolism or the Dopaminstoff pads are correlated to use.
  • drugs prepared from DISCI fragments as tranquilizers or for the therapy of neuropsychiatric disorders, in particular those disorders which interfere with the DISCI metabolism or the Dopaminstoff crisps are correlated to use.
  • a DISC-dependent regulation of the dopamine metabolism which is modulated by the preparation according to the invention, it is conceivable, for example, for use in schizophrenia, (recurrent) depression, bipolar disorder, autism, addictions, Huntington's disease, Tourette syndrome, attention deficit hyperactivity disorder.
  • the preparation of the invention is also applicable to transient or chronic memory disorders such as mild cognitive impairment (MCI), or diseases such as Alzheimer's disease.
  • MCI mild cognitive impairment
  • the preparation according to the invention could be used for the treatment of side effects of certain drugs or substances which affect the dopamine metabolism, by favorably influencing them, including acute poisoning.
  • the preparation according to the invention can be used for the treatment of chronic pain conditions in which dopamine metabolism plays a role, including but not limited to chronic fatigue syndrome, fibromyalgia, "burning mouth syndrome".
  • Dopamine also plays a role in cognitive peculiarities or disorders such as anhedonia, disturbances of social interaction or overall “incentive salience” and the inventive preparation can therefore also be used as a cognitive enhancer in non-ill individuals.
  • the preparation according to the invention is conceivable for the treatment of the following non-brain-specific diseases in which the peripheral dopamine metabolism plays a role, for example cardiovascular diseases, arrhythmias, blood disorders. high pressure, obesity, diabetes, immune regulation, lactation disorders, ammenorrhea, libido and sexual dysfunction.
  • cardiovascular diseases for example cardiovascular diseases, arrhythmias, blood disorders. high pressure, obesity, diabetes, immune regulation, lactation disorders, ammenorrhea, libido and sexual dysfunction.
  • the preparation according to the invention can also influence the proliferation and migration of cells, since this is a core function of DISC1.
  • DISC1 a core function of DISC1.
  • DISC1 or DISC1 fragments are in secreted form suggests that DISC1 may act as a signaling molecule, possibly triggered by certain circumstances such as cellular stress, and may be delivered into the extracellular space by unknown transport mechanisms independent of the endoplasmic reticulum and then binds to specific molecules or receptors. These molecular mechanisms were not expected in the current state of the art because secretion of DISC1 or DISC1 fragments was unknown and considered impossible because DISC1 was classified as a cytosolic cytoskeleton-associated molecule. In this respect, the preparation of the invention justifies a new teaching.
  • the preparation according to the invention may be formulated for subcutaneous, intramuscular, intravenous, intracerebral, intranasal or intraperitoneal administration.
  • subcutaneous and intracerebral administration it is no problem for the person skilled in the art to also provide suitable formulations for the other stated administration possibilities.
  • the invention will be explained in more detail by means of examples and figures:
  • FIG. 1 shows in a bar chart the locomotion behavior of healthy ones
  • FIG. 2 shows, similar to FIG. 1, the effect of (subcutaneous) immunization of
  • FIG. 3 shows the locomotion behavior of amphetamine-sensitized rats determined under similar conditions as in FIG.
  • FIG. 4 shows a (e)
  • Figure 5 shows diagrams A and B showing the effect of DISC 1 immunization on the behavior in the bright field / dark field preference test (black bars, dark field, white bars, bright field).
  • Figure 6 shows a Western blot of cell lysates and the accompanying supernatant expressing DISC 1 and secreting full length DISC1 or a DISC1 fragment into the supernatant
  • Example 1 Examination of rats in an open-field experiment a) Influence of DISC1 on the locomotion behavior in healthy rats
  • TDM trehalose dimycolate
  • MPL monophosphoryl lipid A
  • CWS Cell Wall Skeleton
  • oil squalene
  • the rats were placed in the open-field environment 14 days after the last injection. The rats were observed over a period of 20 minutes and their movement measured by either measuring the total distance covered (Example 1) or dividing the open-field into nine parts (sectors) and the number of crosses from one sector into one adjacent was counted (Example 2). The two measurement methods are equivalent and allow the same statements. Ten rats were examined per group.
  • the results of the experiment are summarized in FIG.
  • the behavior of untreated rats (adjuvant only) is shown in the left bar.
  • the right panel shows the locomotion behavior of the rats injected with the DISC1 fragment (together with the adjuvant).
  • Example la the effect of (subcutaneous) immunization of DISC 1 (598-785) together with adjuvant (ABM-ZK, Linaris, as described) or adjuvant alone as control or only application of PBS as further control, examined for the basal behavior in the open field.
  • the experimental conditions of the open field measurement were as in Example 1a, but the immunized rats were about one year old and the time was determined for the rats to remain in the center of the open field after 15 minutes.
  • the experiment was carried out essentially as described under a). The only difference was that the rats were additionally sensitized with amphetamine before conducting the experiment. Sensitization was performed 2 weeks prior to insertion into the Open-Field container by intraperitoneal (i.p.) administration of 2 mg / kg / rat D-amphetamine daily for five days (dissolved in saline, 1 ml / kg injection volume). After a treatment-free interval of 2 weeks, the open-field testing was then carried out 24 hours after a single injection of 0.5 mg / kg / rat D-amphetamine.
  • DISC1 effects a modulation of the neurochemical processes disturbed by amphetamine sensitization. It is of it assume that such a modulation can be exploited in the treatment of DISC-associated diseases. In particular, for example, depressions associated with a significantly decreasing tendency to activities or movements, a positive effect can be postulated.
  • Example 2 Influence of exogenous DISCI application on the anxiety behavior in healthy rats
  • Wistar rats were stereotactically inoculated with approximately 5 ⁇ g of recombinant DISCI (598-785) protein in the nucleus accumbens (stereotactic coordinates in the head frame (AP: 1.2 mm, ML: ⁇ 0.8 mm, DV: -5.2 mm) Inoculation was used to study the bright field / dark field preference test and the open field test to measure anxiety-induced behavior In the bright field / dark field preference test, the rat is placed in a bright field (61 x 38 x 32 cm) connected to a neighboring dark field measured, which the rat spends in brightfield or darkfield.
  • DISCI recombinant DISCI
  • amphetamine the sensitivity to amphetamine was investigated in the open field experiment after a single intrperitoneal administration of 0.5 mg / kg body weight. Each study period was 15 minutes. The horizontal movement is measured automatically with the TruScan light barrier measuring system (Coulbourn Instruments, Allentown, USA).
  • Figure 4A shows fluorescence microscopy of a brain section of the rat nucleus accumbens stereotactically inoculated with Dylight-labeled (red) recombinant DISCL 598-785. Counterstaining with anti-NeuN antibody, a neuron-specific marker protein. The picture shows that recombinant DISC1 protein was taken up in the cytosol of neurons. Bar 20 ⁇ ⁇ ,
  • Fig. 4B shows a graph of the results of the light-dark preference test two weeks after bilateral inoculation of DyLight-labeled recombinant DISCI (598-785). or control (sham) in the nucleus accumbens of a wild-type rat.
  • the diagram shows that inoculation with DISCI (598-785) has an anxiolytic effect because the residence preference is changed towards the bright field.
  • the rats were screened in with the bright field / darkfield preference test to measure anxiety-induced behavior.
  • the rat is placed in a bright field (61 x 38 x 32 cm), which is connected to an adjacent dark field. During 5 minutes, the time spent by the rat in the bright field or in the dark field is measured.
  • Fig. 5 shows diagrams showing the effect of DISCl immunization on the behavior in the bright field / dark field preference test (black bars, dark field, white bars, bright field).
  • a human neuroblastoma cell line (SHSY-5Y) was retrovirally transfected with the full-length human DISC1 gene (1-854) or a C-terminal human DISC1 fragment fused to the greenfluorescent protein (GFP) can be triggered by the addition of tetrycycline 1 ug / ml ("tet-on") in the cell culture medium (retroviral inducible transfection system pTRE-TIGHT from Clontech / Invitrogen, USA); Tetracycline-induced expression has the advantage over other transient expression systems that the cells do not die as a result of the transfection and thus cytosolic constituents pass conditionally into the cell culture supernatant through cell death.
  • tetrycycline 1 ug / ml retroviral inducible transfection system pTRE-TIGHT from Clontech / Invitrogen, USA
  • Tetracycline-induced expression has the advantage over other transient expression systems that the cells do not die as
  • the cells were then induced for 2 days in serum-free medium with 1 .mu.l / .eta.1 tetracycline and the entire cell culture medium supernatant was finally centrifuged after two days to separate any existing dead cells precipitated with 7g ammonium sulfate / 10 ml of supernatant and separated on an SDS-PAGE gel and displayed in Western blot with standard methods and the antibody 14F2 against human DISC1 protein. As a control, the cell lysates were also examined.
  • Figure 6 shows a Western blot of supernatants (lanes 1-4) or cell lysates (lanes 5-8).
  • the even-numbered lanes 2, 4, 6 and 8 show tetracycline-induced, non-even-numbered lanes 1, 3, 5, 7 uninduced human SHSY-5Y cells.
  • Lanes 2 and 6 show full length human DISC1 protein or human DISC1 (598-854) fragment (lanes 4 and 8), c-terminally fused to green-fluorescent protein (GFP).
  • GFP green-fluorescent protein

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Abstract

L'invention concerne une préparation contenant DISC1 et/ou au moins un fragment de DISC1 à utiliser pour le traitement thérapeutique du corps humain ou animal, la préparation contenant de préférence en outre au moins une substance immunostimulante et ledit fragment de DISC1 étant de préférence DISC1-598-785.
PCT/EP2012/001511 2011-04-13 2012-04-05 Préparation contenant disc1 et/ou au moins un fragment de disc1 à utiliser pour le traitement thérapeutique du corps humain ou animal Ceased WO2012139732A1 (fr)

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DE102011016875.3 2011-04-13
DE102011016875A DE102011016875A1 (de) 2011-04-13 2011-04-13 Zubereitung enthaltend DISC1 und/oder mindestens ein DISC1-Fragment zur Anwendung bei der therapeutischen Behandlung des menschlichen oder tierischen Körpers

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015044679A1 (fr) * 2013-09-27 2015-04-02 The University Court Of The University Of Glasgow Matériels et méthodes pour la modulation du renouvellement de disc1

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058637A2 (fr) 2001-01-24 2002-08-01 Millenium Pharmaceuticals, Inc. Compositions et methodes servant au diagnostic et au traitement de troubles neuropsychiatriques, tels que la schizophrenie
US20050210536A1 (en) 2003-12-05 2005-09-22 Ginns Edward I Modulation of brain pathways and function
WO2009118151A1 (fr) * 2008-03-26 2009-10-01 Carsten Korth Procédés de diagnostic et de traitement de maladies psychiatriques chroniques et marqueurs et cibles pour ces procédés
WO2009154697A2 (fr) 2008-05-28 2009-12-23 Massachusetts Institute Of Technology Activateurs de la voie de la disc-1 dans le contrôle de la neurogenèse

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058637A2 (fr) 2001-01-24 2002-08-01 Millenium Pharmaceuticals, Inc. Compositions et methodes servant au diagnostic et au traitement de troubles neuropsychiatriques, tels que la schizophrenie
US20050210536A1 (en) 2003-12-05 2005-09-22 Ginns Edward I Modulation of brain pathways and function
WO2009118151A1 (fr) * 2008-03-26 2009-10-01 Carsten Korth Procédés de diagnostic et de traitement de maladies psychiatriques chroniques et marqueurs et cibles pour ces procédés
WO2009154697A2 (fr) 2008-05-28 2009-12-23 Massachusetts Institute Of Technology Activateurs de la voie de la disc-1 dans le contrôle de la neurogenèse

Non-Patent Citations (11)

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Title
CHUBB, MOLECULAR PSYCHIATRY, vol. 13, 2008, pages 36
FEATHERSTONE ET AL., PROGRESS IN NEUROPSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, vol. 31, 2007, pages 1556
LELIVELD, BIOCHEMISTRY, vol. 48, 2009, pages 7746 - 7755
LELIVELD: "Oligomer Assembly of the C-Terminal DISC1 Domain (640-854) is controlled by Self-Association Motifs and Disease-Associated Polymorphism S704C", BIOCHEMISTRY, vol. 48, no. 32, 2009, pages 7746 - 7755, XP055030872 *
NICHOLAS J BRANDON ET AL: "Understanding the Role of DISC1 in Psychiatric Disease and during Normal Development", THE JOURNAL OF NEUROSCIENCE, 14 October 2009 (2009-10-14), pages 12768 - 12775, XP055003316, Retrieved from the Internet <URL:http://www.jneurosci.org/content/29/41/12768.full.pdf> [retrieved on 20110721] *
NIWA ET AL., NEU RON, vol. 65, 2010, pages 480
PHILIPP OTTIS ET AL: "Convergence of Two Independent Mental Disease Genes on the Protein Level: Recruitment of Dysbindin to Cell-Invasive Disrupted-In-Schizophrenia 1 Aggresomes", BIOLOGICAL PSYCHIATRY, ELSEVIER SCIENCE, NEW YORK, NY, US, vol. 70, no. 7, 17 March 2011 (2011-03-17), pages 604 - 610, XP028292308, ISSN: 0006-3223, [retrieved on 20110328], DOI: 10.1016/J.BIOPSYCH.2011.03.027 *
SHEN ET AL., J. NEUROSCIENCE, vol. 48, 2008, pages 10893
TOMPPO LIISA ET AL: "Association of variants in DISC1 with psychosis-related traits in a large population cohort.", ARCHIVES OF GENERAL PSYCHIATRY FEB 2009 LNKD- PUBMED:19188535, vol. 66, no. 2, February 2009 (2009-02-01), pages 134 - 141, XP002678795, ISSN: 1538-3636 *
ÜBERSICHT BEI SHEN ET AL., J. NEUROSCIENCE, vol. 48, 2008, pages 10893
YINGWEI MAO ET AL: "Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3[beta]/[beta]-Catenin Signaling", CELL, vol. 136, no. 6, 1 March 2009 (2009-03-01), pages 1017 - 1031, XP055030874, ISSN: 0092-8674, DOI: 10.1016/j.cell.2008.12.044 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015044679A1 (fr) * 2013-09-27 2015-04-02 The University Court Of The University Of Glasgow Matériels et méthodes pour la modulation du renouvellement de disc1
US20160206679A1 (en) * 2013-09-27 2016-07-21 The University Court Of The University Of Glasgow Materials and Methods for Modulating DISC1 Turnover
US9981005B2 (en) 2013-09-27 2018-05-29 The University Court Of The University Of Glasgow Methods for increasing DISC1 in a subject with schizophrenia or bipolar disorder by an antagonist inhibiting DISC1 binding to FBXW7

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