WO2003105910A1 - Produit therapeutique neuronal a base de metallothioneine et methodes therapeutiques - Google Patents

Produit therapeutique neuronal a base de metallothioneine et methodes therapeutiques Download PDF

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Publication number
WO2003105910A1
WO2003105910A1 PCT/AU2003/000735 AU0300735W WO03105910A1 WO 2003105910 A1 WO2003105910 A1 WO 2003105910A1 AU 0300735 W AU0300735 W AU 0300735W WO 03105910 A1 WO03105910 A1 WO 03105910A1
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WO
WIPO (PCT)
Prior art keywords
iia
metallothionein
neuronal
treatment
administration
Prior art date
Application number
PCT/AU2003/000735
Other languages
English (en)
Inventor
Adrian Keith West
Meng Inn Chuah
James Clement Vickers
Roger Steven Chung
Original Assignee
University Of Tasmania
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 University Of Tasmania filed Critical University Of Tasmania
Priority to US10/517,653 priority Critical patent/US8691765B2/en
Priority to NZ537103A priority patent/NZ537103A/en
Priority to AU2003233259A priority patent/AU2003233259B2/en
Priority to EP03727024A priority patent/EP1531905A4/fr
Publication of WO2003105910A1 publication Critical patent/WO2003105910A1/fr

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Classifications

    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to the use of metallothionein as an active ingredient in effecting and enhancing recovery of damaged neuronal tissue, particularly following physical trauma and damage thereto.
  • the invention provides a therapeutic incorporating metallothionein and methods of treatment based thereon.
  • Metallothionein is a naturally occurring peptide, which is present in most cells of the mammalian body. There are many isoforms in humans, but these resolve into four classes; MT-I and MT-II which are expressed widely, MT-III which is mainly found in the brain, and MT-IV which is restricted to specific epithelial sites. MTs are intracellular proteins with occasional nuclear localisation, and although there are persistent reports of extracellular detection of MT, the prevailing dogma is fixed that their physiological role is within cells.
  • MTs are metal binding proteins (61-68 amino acids), which normally bind seven zinc ions, although zinc/copper mixtures have been reported. Some isoforms are rapidly induced in response to increases in zinc or copper levels, and also by a large number of hormones and cytokines, including glucocorticoids, interleukin 1 and 6, interferons and so on. Their exact physiological role is unclear. Early suggestions that they act to prevent accumulation of toxic levels of heavy metals are no longer favoured, and if their role is indeed in metal metabolism, it is more likely that they are involved in the intracellular homeostasis of zinc. However, MTs are efficient scavengers of free radicals and are able to protect DNA and other molecules from oxidation, suggesting that their function may be protective. MTs may be considered intracellular stress proteins which respond to a wide variety of stimuli.
  • MT-I/ ⁇ knockout animals and those which overexpress MT-I and MT-II are phenotypically normal, except for sensitivity and resistance, respectively, to some chemical and physical stresses.
  • MT-III the "brain-specific" class of MT
  • MT-III reduces neuronal survival
  • the applicants have shown that, when MT-III is added to cultured neurons it reduces neurite sprouting.
  • Exogenous MT-III appears to have an opposing effect to MT-DA and it is expected that comparison of their structures will reveal strategies for designing analogues of both which have specific neurotrophic properties. It has been shown that exposure of rat brain lesions to MT-III causes vacuolisation, consistent with extensive neuronal death.
  • metallothionein proteins including MT-IIA, a major human metallothionein of the MT-I/II class.
  • MT-IIA a major human metallothionein of the MT-I/II class.
  • administration of metallothionein to cultured rat neurons increases neuronal survival and enhances the rate of axonal extension.
  • metallothionein enhances regenerative axonal extension into the lesions and replacement of damaged tissue.
  • the use of metallothionein as an active ingredient in neuronal therapy provides a novel method of stimulating neuronal growth and neuronal survival, a novel class of therapeutic agents and a novel method of treatment for a range of neuronally based disease states.
  • metallothionein offers several practical advantages as a therapeutic agent. 1. It is a naturally occurring, non-toxic protein
  • Metallothionein is not post-translationally modified and hence can be easily produced in bacterial or other expression systems 4.
  • Metallothionein is a small peptide (61 amino acids for MT-IIA, 68 amino acids for human MT-III) and it is very likely that a novel analogue which is amenable to chemical synthesis can be designed.
  • the invention provides a method of stimulating neuronal growth comprising exposing a target neuron to metallothionein.
  • the target neuron is preferably placed in direct contact with a metallothionein solution.
  • the target neuron may have suffered physical trauma including lesion or other forms of neurodegeneration.
  • the metallothionein may be selected from any one or a combination of known metallothionein classes including MT-I, MT-II, MT-i ⁇ and MT-IN and the associated isoforms. Most preferably the metallothionein is selected from MT-II including human
  • the metallothionein may be a synthetic analogue which combines structural or physical features of any or all known metallothionein isoforms.
  • the metallothionein may be provided in solution at a concentration of up to about 5 ⁇ g/ml in a neurologically acceptable carrier.
  • Administration of the metallothionein solution may include MT-IIA as the sole active ingredient.
  • any one or a combination of the metallothionein classes and isoforms as detailed above may be used. Where combinations of metallothionein are used the different classes and isoforms may be combined in a single dose. Alternatively, the different classes may be administered sequentially.
  • the administration regime may include initial administration of a solution of MT-IIA followed by a subsequent administration of a solution of MT-III.
  • the administration regime may be limited to MT-IIA alone as the active ingredient.
  • the method of the invention may be applied to a range of compromised neuronal states including diseased states and injuries.
  • the invention provides a method of treatment of any one or a combination of Alzheimers, Parkinsons, Motor Neuron Diseases, head injury, comprising the administration to a patient of a therapeutic including metallothionein as previously described as an active ingredient wherein said therapeutic is applied or administered so as to directly interact with the site of neuronal compromise.
  • a therapeutic composition comprising metallothionein in any one or a combination of isoforms, or as a synthetic metallothionein comprising features of one or more isoforms, as an active ingredient in a pharmaceutically acceptable carrier wherein said carrier is adapted for topical administration to an area of neuronal compromise.
  • composition may be adapted for direct topical application to exposed neurons or for administration to non-exposed neurons by indirect routes including intravenous or intraperitoneal administration, which result in accumulation of metallothionein in the compromised region of the brain or other part of the central nervous system.
  • Figure 1 shows some effects of human MT-IIA on neuronal survival and neurite elongation of cultured rat cortical neurons.
  • Figure 2 shows by immunocytochemistry the effect of human MT-IIA on reactive neurite sprouting following axonal injury.
  • Figure 3 shows by immunocytochemistry the effects of human MT-IIA on reactive neurite sprouting following axonal injury.
  • Figures 4 and 5 show the effect of human MT-IIA on lesions in the rat neocortex formed by physical injury.
  • Figure 6 shows the effect of human MT-III and MT-IIA on neurite formation and initial neurite outgrowth of cultured rat cortical neurons.
  • Figure 7 shows the effect of human MT-III and MT-IIA on the extent and rate of neurite elongation of cultured rat cortical neurons.
  • Figure 8 shows the effect of human MT-III and MT-IIA on the distribution of neurite length of cultured rat cortical neurons.
  • Figure 9A shows immunocytochemistry the effect of human MT-III and MT- IIA on reactive neurite sprouting.
  • Figure 9B shows by immunocytochemistry the effect of human MT-III and MT- II A on reactive axonal growth.
  • Figure 10 shows the quantitative effect of human MT-III and MT-IIA on reactive neurite sprouting and growth.
  • Figure 11 shows by immunohistochemistry the effect of human MT-IIA on axonal sprouting into a lesion site following physical injury in the rat neocortex.
  • Figure 12 shows by immunohistochemistry the effect of human MT-IIA on neuronal injury tract repair.
  • the action of MT-IIA (a major human metallothionein of the MT-I/-II class) in two distinct culture models of rat cortical neurons, and in a rat in vivo model of cortical damage was examined. In culture, it was found that administration of MT-IIA increases neuronal survival, and enhances the rate of axonal extension. In lesioned rat brains, it was found that MT-IIA enhances regenerative axonal growth into the lesion, and replacement of damaged tissue.
  • Rat cortical neurons (El 8) were plated at low density in neurobasal medium + B27 supplement, including 150 ⁇ g/ml of a rat brain extract.
  • Recombinant MT-IIA was produced (the major human metallothionein I/II isoform) in E. coli cultures and reconstituted as a zincthionein (7 moles zinc/mole protein).
  • Rat cortical neurons (El 8) were plated at a higher density in Neurobasal medium + B27 supplement (but without brain extract) and cultured in vitro for 21 days, allowing the formation of neuronal clusters connected by fasciculated axonal bundles.
  • Rat Cortical Injury Model Focal injuries were performed to the adult rat neocortex by insertion of a 25gauge beveled needle into the Par 1 region of the rat somatosensory cortex to a depth of 1.5mm into the brain.
  • the bar graph in Figure 1 A demonstrates that human MT-IIA promotes neuronal survival in the presence of adult rat brain extract (150 ⁇ g/ml) after three days. (P ⁇ 0.01, ANOVA). Accordingly Zn-MT is not detrimental to the survival of cultured neurons.
  • MT-IIA is capable of enhancing neurite elongation of cultured rat cortical neurons without increasing the rate of undesirable neurite sprouting.
  • FIG. 2 a culture of rat cortical neurons was maintained for twenty-one days in order to allow formation of clusters which are interconnected by fasciculated bundles of axons.
  • the axons were cut with a microscapel and a composition as previously described, including recombinant MT-IIA, was added.
  • the immunocytochemical results shown in Figures 2A to 2D show that twelve hours after cutting the neuronal bundles with a microscapel there is a marked retraction by transected neurites from the lesion site (which is indicated with a broken line) of up to lOO ⁇ m.
  • MT-IIA This occurs following lesion by microscapel and after eighteen hours of exposure to MT-IIA the axonal bundles have bridged the region between the clusters. This effect of MT-IIA is a result of a direct topical interaction between the protein, the neurons and the culture medium.
  • FIGS 4, 5, 11 and 12 the action of MT-IIA on a rat model of cortical injury was investigated.
  • the rat model of physical damage to the cortex has been previously developed by the inventors and extensively characterised in terms of neuronal damage, orthology, pathology and subsequent recovery.
  • Figures 4, 5, 11 and 12 show the extent of the physical injury, and microglial invasion of the cavity.
  • MT-IIA administration reduced microglial infiltration and promoted formation of a tissue bridge across the lesion, from the pial surface down.
  • MT-IIA also promoted axonal extension into the lesion site. Very few axonal extensions were seen in the rats treated with vehicle alone (control rats).
  • Figure 4 shows the global location of needle stick injuries as indicated in Panel
  • Figure 6 the effect of MT-III on neurite formation is shown in Figure 6 A in the presence of adult rat brain extract at 150 ⁇ g/ml after three days.
  • Figure 6B shows neurite bearing neurons indicated by the arrows.
  • the percentage of neurite bearing neurons is shown in Figure 6C and the number of neurites per neurite-bearing neuron is shown in Figure 6D. From the above it can be seen that MT-III significantly inhibits neurite outgrowth in both instances at the concentrations tested (p ⁇ 0.01, ANOVA).
  • human MT-IIA had no effect on initial neurite outgrowth over three days. As assessed by both the percentage of neurite bearing neurons or as detailed in Figure 6F, the number of neurites per neurite-bearing neurons. Referring now to Figure 7, it has been shown that human MT-III prolongs the process of neurite retraction from 0-2 and 2-4 hours after plating as can be seen with reference to Figure 7A. Following this, the rate of neurite elongation is reduced. Referring now to Figure 7B, in contrast to this, application with human MT-IIA significantly increases the rate of neurite elongation.
  • the transection site is indicated by a broken line and there is a large area of retraction away from this line.
  • Sprouting neurites are indicated by arrows.
  • the MT- IIA treatment increased both the number and length of reactive sprouts following injury and this is detailed in Figure 9A Panel E which details the vehicle example and 9A Panel F which indicates the MT-IIA example at l ⁇ g/ml (check, please).
  • MT-IIA further promoted axonal sprouting into the lesion site at both the pial layer as shown in Figure 11C and deeper cortical layers shown in Figure 1 ID.
  • very few axonal sprouts were visualised in control rats as shown at the pial level in Figure 1 IE and deeper cortical layers as shown in Figure 1 IF.
  • the arrow heads indicate the injury tract.
  • Figure 12 shows details of further experimental work on brain sections at 7 days post injury.
  • vehicle treated rats the injury tract was smaller compared to four days post injury shown in Figure 11; although it had not completely closed over, a degree of reactive sprouting is evident in all animals at this time point as shown in Figure 12A.
  • Reactive processes exhibited greater SMI-312 reactivity than uninjured neuronal processes in surrounding neural tissue.
  • Reactive astrocytes also aligned along the borders of the injury tract as shown in Figure 12B.
  • the entire injury tract had closed over, and was demarcated only by a fine line of ferritin immunoreactivity as shown in Figure 12C.
  • Reactive astrocytes also enclose the injury tract, and were found at lower density in adjacent uninjured tissue shown in Figure 12D.
  • MT-IIA treated animals numerous reactive axonal processes were observed as shown by the arrows within the injury tract at both deeper cortical levels shown in Figure 12E and pial levels shown in Figure 12F .

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Abstract

L'invention concerne une méthode de stimulation de la croissance ou de la réparation neuronale, qui consiste à exposer un neurone ou une zone neuronale cible à une solution d'isoforme de métallothionéine MT-IIA.
PCT/AU2003/000735 2002-06-13 2003-06-13 Produit therapeutique neuronal a base de metallothioneine et methodes therapeutiques WO2003105910A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/517,653 US8691765B2 (en) 2002-06-13 2003-06-13 Metallothionein based neuronal therapeutic and therapeutic methods
NZ537103A NZ537103A (en) 2002-06-13 2003-06-13 Metallothionein based neuronal therapeutic and therapeutic methods
AU2003233259A AU2003233259B2 (en) 2002-06-13 2003-06-13 Metallothionein based neuronal therapeutic and therapeutic methods
EP03727024A EP1531905A4 (fr) 2002-06-13 2003-06-13 Produit therapeutique neuronal a base de metallothioneine et methodes therapeutiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPS2958A AUPS295802A0 (en) 2002-06-13 2002-06-13 Metallothionein based neuronal therapeutic and therapeutic methods
AUPS2958 2002-06-13

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WO2003105910A1 true WO2003105910A1 (fr) 2003-12-24

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AU (1) AUPS295802A0 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007110079A2 (fr) * 2006-03-29 2007-10-04 Enkam Pharmaceuticals A/S Administration ciblée de ligands du récepteur fgrf au cerveau
WO2007093177A3 (fr) * 2006-02-14 2007-12-21 Vladimir Berezin Fragments de peptides derives de la metallothioneine
CN106552258A (zh) * 2016-02-15 2017-04-05 聊城市奥润生物医药科技有限公司 Zn7MT3在防治阿尔茨海默症中的应用

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US5268175A (en) * 1992-02-17 1993-12-07 Indena Spa Cosmetic and/or pharmaceutical compositions and methods for their use
US5431923A (en) * 1992-02-17 1995-07-11 Indena S.P.A. Topical cosmetic and/or pharmaceutical compositions
WO1998031795A2 (fr) * 1997-01-17 1998-07-23 Incyte Pharmaceuticals, Inc. Nouvelle metallothioneine humaine
FR2813529A1 (fr) * 2000-09-06 2002-03-08 Provital S A Composition cosmetique et/ou pharmaceutique comprenant une metallothioneine
WO2002043507A2 (fr) * 2000-11-30 2002-06-06 The Health Research Institute Complements nutritifs et procedes de traitement de l'autisme et de prevention de l'apparition de l'autisme

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5268175A (en) * 1992-02-17 1993-12-07 Indena Spa Cosmetic and/or pharmaceutical compositions and methods for their use
US5431923A (en) * 1992-02-17 1995-07-11 Indena S.P.A. Topical cosmetic and/or pharmaceutical compositions
WO1998031795A2 (fr) * 1997-01-17 1998-07-23 Incyte Pharmaceuticals, Inc. Nouvelle metallothioneine humaine
FR2813529A1 (fr) * 2000-09-06 2002-03-08 Provital S A Composition cosmetique et/ou pharmaceutique comprenant une metallothioneine
WO2002043507A2 (fr) * 2000-11-30 2002-06-06 The Health Research Institute Complements nutritifs et procedes de traitement de l'autisme et de prevention de l'apparition de l'autisme

Non-Patent Citations (6)

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Title
ALDARD P.A. ET AL.: "Increased density of metallothionein I/II-immunopositive cortical glial cells in the early stages of Alzheimer's disease", NEUROBIOLOGY OF DISEASE, vol. 5, no. 5, 1998, pages 349 - 356, XP008102925 *
ASCHNER M.: "The functional significance of brain metallothioneins", THE FASEB JOURNAL, vol. 10, no. 10, 1996, pages 1129 - 1136, XP001189688 *
LUI E. ET AL.: "Metals and the liver in Alzheimer's disease: an investigation of hepatic zinc, copper, cadmium and metallothionein", J. AM. GERIATR. SOC., vol. 38, no. 6, 1990, pages 633 - 639, XP008100911 *
RICHARZ A.-N. ET AL.: "Speciation analysis of trace elements in the brains of individuals with Alzheimer's disease with special emphasis on metallothioneins", ANAL. BIONAL. CHEM., vol. 372, no. 3, 2002, pages 412 - 417, XP008099934 *
See also references of EP1531905A4 *
ZAMBENEDETTI P. ET AL.: "Metallothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer's disease", JOURNAL OF CHEMICAL NEUROANATOMY, vol. 15, no. 1, 1998, pages 21 - 26, XP002286743 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093177A3 (fr) * 2006-02-14 2007-12-21 Vladimir Berezin Fragments de peptides derives de la metallothioneine
EP2412726A2 (fr) 2006-02-14 2012-02-01 University Of Tasmania Through The Menzies Research Institute Fragments de peptides dérivés de la métallothionéine
EP2412727A2 (fr) 2006-02-14 2012-02-01 University Of Tasmania Through The Menzies Research Institute Fragments de peptides dérivés de la métallothionéine
EP2412727A3 (fr) * 2006-02-14 2012-04-25 University Of Tasmania Through The Menzies Research Institute Fragments de peptides dérivés de la métallothionéine
EP2412726A3 (fr) * 2006-02-14 2012-05-23 University Of Tasmania Through The Menzies Research Institute Fragments de peptides dérivés de la métallothionéine
US8618060B2 (en) 2006-02-14 2013-12-31 University Of Tasmania Metallothionein-derived peptide fragments
US9518089B2 (en) 2006-02-14 2016-12-13 University Of Tasmania Metallothionein-derived peptide fragments
US10100100B2 (en) 2006-02-14 2018-10-16 University Of Tasmania Metallothionein-derived peptide fragments
WO2007110079A2 (fr) * 2006-03-29 2007-10-04 Enkam Pharmaceuticals A/S Administration ciblée de ligands du récepteur fgrf au cerveau
WO2007110079A3 (fr) * 2006-03-29 2008-03-20 Enkam Pharmaceuticals As Administration ciblée de ligands du récepteur fgrf au cerveau
CN106552258A (zh) * 2016-02-15 2017-04-05 聊城市奥润生物医药科技有限公司 Zn7MT3在防治阿尔茨海默症中的应用
WO2017140212A1 (fr) * 2016-02-15 2017-08-24 聊城市奥润生物医药科技有限公司 Utilisation de zn7mt3 dans la prévention et le traitement de la maladie d'alzheimer

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NZ537103A (en) 2007-11-30
EP1531905A1 (fr) 2005-05-25
AUPS295802A0 (en) 2002-07-04
EP1531905A4 (fr) 2010-12-22

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