WO1999024572A1 - Genes with restricted expression in mesencephalic dopaminergic neurons - Google Patents
Genes with restricted expression in mesencephalic dopaminergic neurons Download PDFInfo
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- WO1999024572A1 WO1999024572A1 PCT/NL1998/000652 NL9800652W WO9924572A1 WO 1999024572 A1 WO1999024572 A1 WO 1999024572A1 NL 9800652 W NL9800652 W NL 9800652W WO 9924572 A1 WO9924572 A1 WO 9924572A1
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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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
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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
- C07K14/475—Growth factors; Growth regulators
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to the field of neurology, psychiatry, neuropathology and neuropharmacology, more specifically to neurological disorders such as Parkinson's disease and tardive dyskinesia, and psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression, and other disorders related to malfunctioning of the mesencephalic dopaminergic (mesDA) system.
- neurological disorders such as Parkinson's disease and tardive dyskinesia
- psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression, and other disorders related to malfunctioning of the mesencephalic dopaminergic (mesDA) system.
- meDA mesencephalic dopaminergic
- the mesDA system consists of groups of neurons located in the substantia nigra (SN) and ventral tegmental area (VTA) of the mesencephalon of all mammals. These neurons project axons towards a number of forebrain areas, including cortical, striatal and limbic brain areas, where dopamine (DA) is acting as neurotransmitter regulating a variety of brain functions. Brain functions regulated by mesDA neurons include the control of movement and behaviours. A number of neurological and psychiatric disorders are implicated as caused by a malfunctioning mesDA system. Among these neurological disorders one finds extra-pyramidal motor disorders such as degeneration of mesDA neurons which is the cause of Parkinson's disease.
- Parkinson's disease patients may differ.
- the striato-nigral pathway degenerates causing motor disturbance and uncontrolled movement.
- the mesDA system is involved in tardive diskinesia, which is a movement disorder manifested by involuntary movements, often seen as side effect of anti-psychotic drug treatment.
- psychiatric disorders such as schizophrenia are known, where a fundamental, developmental malfunctioning of the mesDA system is a proposed aetiology. Manic-depression is associated with the mesDA system as well; just as well as addictive behaviours, most importantly drug addiction, are linked to the activity of the mesDA system.
- Malfunctions of the mesDA system may be of a various nature; for example its development can be affected resulting in a inappropriate innervation of target brain areas or a failure to synthesise dopamine . Furthermore, malfunctioning can be related to the maintenance of the mesDA system; an intrinsic drive of gene expression may be necessary to maintain functional integrity and protect against degradation by radicals or other noxious stimuli. Neurological disorders affecting movement related to the jnesDA system are relatively well understood, in contrast to psychiatric disorders related to the mesDA system. However, considering the relative importance of this group of disorders, a need exists to be able to better diagnose and treat these diseases. For example, Parkinson's disease is a degenerative neurologic disorder that effects several millions of people.
- Neuropathological diagnosis of Parkinson's disease is currently based on examination of post-mortem brain sections macroscopically and microscopically after HE staining looking for Lewy bodies, or by immunohistochemistry for tyrosine hydroxylase, an enzyme critical for catecholamine (dopamine, noradrenalin, adrenalin) production.
- a major disadvantage is that an accurate diagnosis can only be made after the patient has died; there is currently no other way of diagnosing this disease in an earlier phase, except by a diagnosis on more- or-less well understood clinical and neuropsychological symptoms. As a consequence, patients are often diagnosed late in the course of the disease.
- An additional disadvantage is the presence of tyrosine hydroxylase in other neurons than those affected by Parkinson's disease, which can lead to faulty diagnosis if the mesDA neurons are not accurately localised.
- Parkinson's disease may be genetically predisposed, whereby several different phenotypes have been associated with autosomal (dominant as well as recessive) or X- or Y-linked genetic causes; Lewy body Parkinson's disease is one of these examples. It seems possible, indeed likely, that parkinsonism is heterogeneous, with some mendelian forms of the disease. A genetic link between patients with Parkinson's disease and patients with manic depression has been reported as well. Yet other causes of Parkinson's disease are thought to be intoxications with toxic substances such as meperidine and other neurotoxic xenobiotics, and metal ions such as manganese .
- Parkinson's disease associated with homozygosity for a mutation in a gene encoding a part of a potassium channel bears no relevance to human disease, said genetic defect is not found with human patients.
- mesDA cells injected with 6-hydroxydopamine (6-OHDA) in the corpus striatum or sybstantia nigra/VTA of the rat brain This model, however, depends on the creation of irreversible lesions in the mid-brain of the rat, creating more or less serious losses of dopaminergic neurons. No rat can be considered having been given the same lesion, consequently, this model is inaccurate, and gives no insight in development of the disease.
- Nurrl- deficient mice Another suggested model entails the use of Nurrl- deficient mice.
- Nurrl is expressed in the mid-brain of mice during embryonic development, but expression is not restricted to this area.
- Nurrl activity during embyronic development is thought to be part of a very generalised signaling mechanism that cells use.
- Nurrl knock-out mice fail to develop mesDA neurons, making them putative candidates for studying neurological disorders related to the mesDA system, such as Parkinson's disease.
- Nurrl expression is not restricted to mesDA neurons but is also part of an overall signalling mechanism that cells use. It is evidently needed in other organ systems more central to the viability of the mice involved. Homozygous Nurrl knock-out mice die within two days after birth and are therefore not available as an animal model.
- heterozygous Nurrl knock-out mice show reduced dopamine levels, they do not show apparent histological or behavioural abnormalities, again making them unsuited for use as an animal model.
- knock-out dopamine deficient mice wherein the tyrosine hydroxylase gene was disrupted, these die within two weeks after birth, probably also because the tyrosine hydroxylase gene is essential for viability of many more cells and tissues.
- GDNF glial cell-line derived neurotrophic factor
- GDNF knock-out mice have no lesions in the mesDA system but fail to develop kidneys and have lesions in the enteric nervous system instead.
- mesDA related genes that for example can be used to create an animal model to be used to study neurological disorders, are not available.
- the invention provides a mesDA related nucleic acid and means and methods which allow studying neurological disorders related to the mesDA system. The invention provides methods and means of diagnosing such neurological disorders and suitable animal models wherein the mesDA system and its development can be studied.
- the invention provides an isolated and/or recombinant nucleic acid or a specific fragment, homologue or derivative thereof, corresponding to a gene with restricted expression in mesencephalic dopaminergic neurons.
- the definition 'nucleic acid' is used, both RNA and DNA, in single or double-stranded fashion, and nucleic acid hybridising thereto is meant.
- a specific fragment, homologue or derivative of a nucleic acid provided by the invention is meant as well.
- the meaning of 'specific fragment', 'homologue' and 'derivative' is clear to those skilled in the art.
- nucleic acid or part thereof that is functionally or structurally related to or hybridising with a distinct nucleic acid or fragment thereof.
- a nucleic acid provided by the invention corresponds to a gene or its gene product (nucleic acid and/or protein) that forms a part of the regulatory cascade for the embryonic development and the maintenance in adulthood of the mesencephalic dopaminergic neuron (mesDA) system.
- a characteristic feature of a regulatory cascade concerns the fact that a variety of genes and gene products act in concert. These genes act, often within a certain time span, some synchronously, others sequentially, to activate tissue and/or cell specific gene expression and differentiation, thereby allowing embryonic cells of yet unspecified or partly specified nature to further differentiate into a more mature cell tissue and/or organ.
- genes for example encode nuclear hormone receptors or homeodomain proteins, which are transcription factors that regulate major developmental processes.
- the invention provides an isolated and/or recombinant nucleic acid or a specific fragment, homologue or derivative thereof, corresponding to a gene that is functional in the regulatory cascade leading to the differentiation of mesDA neurons.
- the regulatory cascade is involved in restricting the future nature of the embryonic cell, whereby the cell is loosing its general, unspecified nature and gains specific characteristics and properties.
- This differentiation process is regulated by a cascade of gene and gene product interactions, whereby generally interactions that come in a later phase (downstream) are of a more restricted nature then those interactions that occur earlier (upstream) .
- Upstream activators or regulators in general show a broad expression, whereby activity can be detected in a broad range of (as yet undifferentiated) cells.
- a nucleic acid that is corresponding to a gene with restricted expression corresponds to a gene which activates or regulates a later phase in a regulatory cascade; whereby its expression (insofar as it is related to the development of that specific cell type) is restricted to one or a few specific cell types in that phase of development.
- Expression of upstream regulators is in general less restricted than the expression of downstream regulators .
- the invention provides a nucleic acid corresponding to a gene that is involved in the regulatory cascade of the embryonic development of the mesDA system. Said gene is involved in the regulatory cascade, activating a programme for mesDA-specific gene expression and differentiation.
- An example of a nucleic acid (of which a corresponding sequence is given in figure 5) provided by the invention relates to a Ptx3 gene.
- the invention further provides a method to identify a gene related to the regulatory cascade involved in the development of the mesDA system.
- One example of such a -" method according to the invention is using mutant or even transgenic cells or animals (54; 55) .
- mesDA cellular markers in for example a transgenic or mutant cell or animal provided by the invention (for example an animal expressing ectopic Ptx3 and/or a functional mutant of Ptx3 or a knock-out mutant) we can examine what the influence of said gene on the expression of other mesDA genes is.
- changes in the expression patterns are observed by making libraries of the expressed mRNAs which can be subtracted from each other. This yields the specific expressed mRNA in the wild type cell or animal, as compared to the transgenic or mutant cell or animal.
- a similar approach is the differential display where one performs PCR on both species mRNA and compares the results in respect to each other.
- the bands that appear specifically in the wild type, as compared to the mutant or transgenic cell or animal, represent a nucleic acid that is under control of for example Ptx3.
- This specific PCR product is sequenced and analysed to further determine a nucleic acid sequence of a mesDA gene.
- Yet another example of a method to identify a gene related to the regulatory cascade involved in the development of the mesDA system entails the use of methods to study protein interaction in the regulatory cascade.
- Ptx3 interacting proteins are identified. Methods studying such protein interaction are known in the art .
- the interactions of different domains of for example Ptx3 are studied in a yeast two-hybrid screen. This system is based on an approach that the protein of interest can interact with a library of other proteins.
- a functional transcription activation signal is generated that expresses a marker in the yeast.
- These marker expressing yeast is isolated and amplified. From such clonal lines the plasmids are retrieved which produce the cDNA of the interacting protein, thereby generating the sequence of yet another gene involved in the regulatory cascade and restricted expression of the mesDA system.
- protein-DNA-binding is determined by in-vitro UV-cross linking experiments during a DNA -binding experiment. Protein complexes are examined by Western analysis using specific antibodies for expected target proteins. Further studies of a gene related to the regulatory cascade of the embryonic development of the mesDA system are for example achieved by a method, such as expression studies during embryonic development, that are further explained in detail in the experimental part of this description.
- the invention provides an isolated and/or recombinant nucleic acid, or a specific fragment, homologue or derivative thereof, corresponding to a gene being related to neurological disorders such as Parkinson's disease and tardive dyskinesia and psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression.
- An example of a nucleic acid provided by the invention is a nucleic acid encoding (parts of) a Ptx3 gene or homologue which is expressed in neurons of the mesDA system of vertebrates .
- the invention further provides a method identifying a gene related to neurological disorders such as Parkinson's disease and tardive dyskinesia, and psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression.
- a gene related to neurological disorders such as Parkinson's disease and tardive dyskinesia
- psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression.
- Expression of for example a Ptx3 gene in neurons ' of the mesDA system is maintained in adult individuals, whereas expression is reduced, enhanced or absent in neurons of the mesDA system of individuals having a neurological disorder related to dysfunctioning of neurons of the mesDA system.
- the invention provides a nucleic acid corresponding to a gene which is related to a homeodomain gene, preferably being a bicoid-related homeodomain gene, with restricted expression in the mesDA system and related to homeodomain protein- associating proteins and homeodomain-heterodimerizating partnbers.
- a gene provided by the invention is given with the Ptx3 gene in the experimental part, wherein in figure 1 a (bicoid-related) homeodomain is depicted.
- Ptx3 is expressed in the mesDA system during development, where it activates a programme for mesDA specific gene expression and differentiation, and maintains its expression in healthy neurons of adult individuals .
- a preferred embodiment of the invention provides a nucleic acid according to the invention which gene is of vertebrate origin.
- the majority of L-DOPA- and DA-ir perikarya is, however, situated in the mesencephalic tegmentum, in the area ventralis of Tsai and in the nucleus tegmenti pedunculo- pontinus, pars compacta which are the avian homologues of, respectively, the ventral tegmental area and the substantia nigra of mammals.
- the analog system is found in the mid brain tegmentum.
- a preferred embodiment of the invention provides a nucleic acid hybridising to (parts of) a nucleic acid with a nucleic acid sequence as listed in figure 5.
- a nucleic acid hybridising with a part of DNA of a Ptx3 gene of rat origin For example, the invention provides a nucleic acid hybridising to a nucleic acid present in mouse embryonic tissue being expressed during embryonic development and showing restricted expression in neurons of the mesDA system, or hybridising to a nucleic acid with for example a genomic organisation as shown in figure 6.
- the invention provides a nucleic acid hybridising to a nucleic acid present in human brain ra 1 ⁇ d r-i ⁇ d
- allelic variation are found in humans by locating mutations, or other variations, in the Ptx3 gene in humans by using methods such as sequencing, restriction fragment length polymorphism, SSCP analysis and others that are available in the art (see for example 49; 50 ; 51 ;52 ; 53 ) .
- Cloning of cDNA or genomic DNA of patients gives the opportunity to screen for mutations in patients that are affected in the mesDA system.
- PCR cloning of the genomic DNA of the patients and sequencing it mutations and variations are easily assessed.
- a more broader approach is to study restriction fragment polymorphisms. By this technique mutations and variations in the gene are found due to altered appearance of restriction analysis followed by Southern hybridisation of the genomic DNA.
- a more sensitive method is the single-strand conformation polymorphism.
- variations in a given gene are detected by the altered characteristics of the single stranded DNA fragment spanning the gene of interest.
- the invention provides a method for determining expression of a gene using a nucleic acid according to the invention.
- a preferred embodiment of the invention is wherein said gene is related to neurological disorders or wherein said expression is determined in neurons.
- An example of a method provided by the invention is the detection of Ptx3 expression in the mesDA system of adult rat or human brain tissue, for example in neurons in the substantia nigra or ventral tegmental area, as further explained in the experimental part of the description.
- Another example provided by the invention is the detection of restricted Ptx3 expression in embryonic mouse tissue sections, for example in lens, sclerotome, tongue and brain tissue at various stages of embryonic development .
- the invention also provides a protein or peptide comprising an amino acid sequence encoded by a nucleic acid according to the invention.
- An example provided by the invention is a protein or peptide or fragment thereof comprising at least a part of a Ptx3 amino acid sequence as shown in the experimental part of the description, for example in figure 1.
- a fusion protein for example of a part of GDNF and part of Ptx3 , created using cloning techniques as known in the art.
- an DNA construct encoding such a fusion protein which contains a part of the GDNF cDNA and a part of the Ptx3 cDNA fused together in the proper reading frame, is created by isolating both coding regions (by PCR) and cloning parts of them in the correct reading frame after each other.
- the resulting DNA fragment can be placed in a eukaryotic expression vector which contains the necessary signals to ensure a stable mRNA transcript.
- the protein is expressed in an eukaryotic cell-line and purified by use of standard purification methods.
- Yet another example entails prokaryotic expression of recombinant protein, for example Ptx3 protein, by cloning cDNA in a prokaryotic expression vector, which optionally fuses a highly expressed protein to for example Ptx3.
- a resulting (chimeric) protein can be produced in large amounts and purified. The resulting protein or peptide can be injected into an animal to raise antibodies.
- the invention provides a natural or synthetic antibody directed against a protein or peptide according to the invention.
- Antibodies poly- or monoclonal
- Antibodies are produced as indicated above, or by other methods known in the art, for example by phage-display or related techniques whereby so- called synthetic antibodies are produced.
- a polyclonal antiserum (Ptx3-Abms01) raised in rabbit against a C-terminal portion of the rat Ptx3 protein fused to bacterial gluthathion-S-transferase has been obtained.
- Ptx3-Abms01 recognizes Ptx3 of rat, mouse and human.
- Ptx3 protein of these species are detected on Western Blots of biological X SH rH ⁇ O ar ⁇
- the invention for example provides a method to trace or detect mesDA degeneration in human CSF.
- Ptx3 cDNA is used as an exclusive marker for mesDA neurons by using parts of the DNA as in-situ hybridisation probes or use of the Ptx3 antibodies in immunological detection methods. Specific antibodies are also used to detect Ptx3 proteins in other material like CSF, by usage of immuno-precipitation.
- the presence of Ptx3 mRNA or protein in CSF originates from damaged mesDA neurones .
- Ptx3 protein is detected in CSF of patients for diagnostic purposes by radioimmunoassay (RIA) or by Western blotting according to established principles. CSF of patients is obtained by lumbar punction.
- Aliquots of CSF are for example tested in a (radio) -immunoassay using a specific radioactive, fluorescent or enzymatic label, and for example recombinant Ptx3 protein as tracer and/or recombinant Ptx3 protein as standard, according to standard procedures.
- the detection of Ptx3 in CSF samples is for example based on the specific displacement of or competition with labelled Ptx3 , but other approaches for immunoassays are also known in the art. For example, by Western blotting a protein fraction of a concentrated CSF sample is separated according to size by polyacrylamide gel electrophoresis, transferred to a nitrocellulose or nylon membrane, and incubated with a pPtx3 specific antibody.
- the detection of Ptx3 in CSF samples is based on the specific staining of Ptx3 protein on the membrane .
- the invention also provides use of a method according to the invention to detect or diagnose a neurological disorder, such as Parkinson's disease and tardive dyskinesia and psychiatric disorders such as schizophrenia, addiction and affective disorders, like manic depression, or use of a method according the invention to test or develop specific medication for the treatment of a neurological disorder. Diagnosing a disease or developing medication for it is possible when a pathogenetic mechanism has been elucidated ⁇ rd 4H d Q d d xi 0 d . . ⁇ -H ⁇ H CQ d
- the invention provides use of a cell according to the invention for the treatment of a neurological disorder, such as Parkinson's disease and tardive dyskinesia, and psychiatric disorders such as schizophrenia, addiction and affective disorders, like manic depression.
- a neurological disorder such as Parkinson's disease and tardive dyskinesia
- psychiatric disorders such as schizophrenia, addiction and affective disorders, like manic depression.
- Cells such as undifferentiated nerve cells of various origin (foetal or porcine cells are a possibility) can be transfected with for example (parts of) Ptx3 nucleic acid, optionally comprising additional nucleic acid derived of another gene, such as the GDNF gen.
- Such cells are converted in dopamine producing cells that can be used to replace those that are for example damaged by Parkinson's disease.
- the invention provides a pharmaceutical composition comprising a protein or peptide according to the invention and its use for the treatment of a neurological disorder, such as Parkinson's disease and tardive dyskinesia, and psychiatric disorders such as schizophrenia, addiction and affective disorders, like manic depression.
- a pharmaceutical composition is a composition comprising a protein or peptide or fragment thereof comprising at least a part of a Ptx3 amino acid sequence as shown in the experimental part of the description, for example in figure 1, or a fusion protein, for example of a part of GDNF and part of Ptx3.
- the invention provides a pharmaceutical composition comprising an expression vector according to the invention, and its use for the treatment of a neurological disorder, such as Parkinson's disease and tardive dyskinesia, and psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression.
- a neurological disorder such as Parkinson's disease and tardive dyskinesia
- psychiatric disorders such as schizophrenia, addiction and affective disorders like manic depression.
- compositions comprising a a viral vector or a targeting vector specifically directed at a target locus in a genome of an experimental animal or human.
- a vector allows in vivo "" targeting of other proteins to mesDA neurons by using regulatory regions or promotor regions of for example the Ptx3 gene .
- a viral vector can be constructed for example for in vivo viral gene transfer in patients.
- Viruses engineered to transfer genes to in vivo tissues e.g. adeno, AAV, retrovirus
- a pharmaceutical composition comprising a vector virus according to the invention is for example delivered locally in the substantia nigra of patients for example by micro- cannulation and injection. The invention is further explained in the experimental part which cannot be seen as limiting the invention.
- Nuclear hormone receptor genes or homeodomain genes specify cell fate and positional identity in embryos throughout the animal kingdom.
- the homeodomain is a DNA binding motif which is characteristic and strongly conserved among the homeodomain proteins.
- the specificity of homeodomain binding to its target is based on distinct DNA binding properties of the homeodomain sequence and assembly with other proteins .
- Protein-protein interactions can involve both specific residues within the homeodomain itself and other regions of the protein, as has been suggested for the regions immediately C- and N-terminal to the homeodomain.
- the Ptx proteins are found to be most closely related to the Caenorhabdi tis elegans Unc-30 protein.
- the Paired-like proteins were found to share a 14 amino acid motif located 3 ' of the homeodomain, with the proteins which may represent a DNA binding element or a site of protein-protein interaction playing a role in the specificity of the homeodomain protein function.
- the patterning of the developing mammalian brain is thought to involve cascades of signalling molecules and transcription factors, but the mechanisms for generation of distinct neuronal cell types during terminal differentiation are still largely speculative (1,2). Yet, the specification of individual neuronal phenotypes underlies the assembly of neural circuits essential for brain function.
- the mesDA system consists of a limited set of neurons that are well- defined anatomically and functionally (3-5) . Their specific degeneration in Parkinson's disease reveals their functional properties in control of behaviour and movement as well as a unique vulnerability (6-10) .
- RNA from hypothalamic fragments of the adult rat brain were subjected to reverse transcriptase/PCR with primers based on brain expressed homeobox genes: upstream: 5'- GMRSCGMSAVMGSACMMBCTTYAC -3', downstream: 5'-
- the annealing temperature was XI - ⁇ ⁇ -*. ⁇ CQ d
- Ptx3 is a candidate gene involved in such mechanisms. Furthermore, the function of Ptx3 can be exploited for manipulation of dopaminergic cells in vi tro in preparation of tissue grafting, an experimental therapy for Parkinson patients (41-43) .
Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU11796/99A AU1179699A (en) | 1997-11-11 | 1998-11-11 | Genes with restricted expression in mesencephalic dopaminergic neurons |
EP98954850A EP1029051A1 (en) | 1997-11-11 | 1998-11-11 | Genes with restricted expression in mesencephalic dopaminergic neurons |
CA002309383A CA2309383A1 (en) | 1997-11-11 | 1998-11-11 | Genes with restricted expression in mesencephalic dopaminergic neurons |
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EP97203511.7 | 1997-11-11 | ||
EP97203511 | 1997-11-11 |
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WO1999024572A1 true WO1999024572A1 (en) | 1999-05-20 |
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EP (1) | EP1029051A1 (en) |
AU (1) | AU1179699A (en) |
CA (1) | CA2309383A1 (en) |
WO (1) | WO1999024572A1 (en) |
Cited By (1)
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WO2007047699A1 (en) * | 2005-10-17 | 2007-04-26 | Epigenomics Ag | Method and nucleic acids for the improved treatment of breast cancers |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5438121A (en) * | 1989-08-30 | 1995-08-01 | Max-Planck-Gesellschaft zur Foderund der Wissenschaften e.V. | Brain derived neurotrophic factor |
-
1998
- 1998-11-11 WO PCT/NL1998/000652 patent/WO1999024572A1/en not_active Application Discontinuation
- 1998-11-11 CA CA002309383A patent/CA2309383A1/en not_active Abandoned
- 1998-11-11 EP EP98954850A patent/EP1029051A1/en not_active Withdrawn
- 1998-11-11 AU AU11796/99A patent/AU1179699A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5438121A (en) * | 1989-08-30 | 1995-08-01 | Max-Planck-Gesellschaft zur Foderund der Wissenschaften e.V. | Brain derived neurotrophic factor |
Non-Patent Citations (7)
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2007047699A1 (en) * | 2005-10-17 | 2007-04-26 | Epigenomics Ag | Method and nucleic acids for the improved treatment of breast cancers |
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CA2309383A1 (en) | 1999-05-20 |
EP1029051A1 (en) | 2000-08-23 |
AU1179699A (en) | 1999-05-31 |
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