Diagnostic and therapeutic use of a golgi protein for neurodegenerative diseases
OwnerHeinz Von der Kammer, Johannes Pohlnerinventors
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Abstract
The present invention discloses the differential expression of golgin-245 in specific brain regions of Alzheimer's disease patients. Based on this finding, this invention provides a method for diagnosing or prognosticating a neurodegenerative disease, in particular Alzheimer's disease, in a subject, or for determining whether a subject is at increased risk of developing such a disease. Furthermore, this invention provides therapeutic and prophylactic methods for treating or preventing Alzheimer's disease and related neurodegenerative disorders using a gene coding for golgin-245. A method of screening for modulating agents of neurodegenerative diseases is also disclosed.
Claims20
A method of diagnosing or prognosticating a neurodegenerative disease in a subject, or determining whether a subject is at increased risk of developing said disease, comprising determining a level and/or an activity of
- (i) a transcription product of a gene coding for golgin-245, and/or
- (ii) a translation product of a gene coding for golgin-245 and/or
- (iii) a fragment, or derivative, or variant of said transcription or translation product,
- in a sample from said subject and comparing said level and/or said activity to a reference value representing a known disease or health status, thereby diagnosing or prognosticating said neurodegenerative disease in said subject, or determining whether said subject is at increased risk of developing said neurodegenerative disease.
A method of monitoring the progression of a neurodegenerative disease in a subject, comprising determining a level and/or an activity of
- (i) a transcription product of a gene coding for golgin-245, and/or
- (ii) a translation product of a gene coding for golgin-245, and/or
- (iii) a fragment, or derivative, or variant of said transcription or translation product,
- in a sample from said subject and comparing said level and/or said activity to a reference value representing a known disease or health status, thereby monitoring the progression of said neurodegenerative disease in said subject.
A method of evaluating a treatment for a neurodegenerative disease, comprising determining a level and/or an activity of
- (i) a transcription product of a gene coding for golgin-245, and/or
- (ii) a translation product of a gene coding for golgin-245, and/or
- (iii) a fragment, or derivative, or variant of said transcription or translation product,
- in a sample from a subject being treated for said disease and comparing said level and/or said activity to a reference value representing a known disease or health status, thereby evaluating said treatment for said neurodegenerative disease.
A kit for diagnosing or prognosticating a neurodegenerative disease, in particular Alzheimer's disease, in a subject, or determining the propensity or predisposition of a subject to develop such a disease, said kit comprising:
- (a) at least one reagent which is selected from the group consisting of (i) reagents that selectively detect a transcription product of a gene coding for golgin-245 and (ii) reagents that selectively detect a translation product of a gene coding for golgin-245, and
- (b) an instruction for diagnosing, or prognosticating a neurodegenerative disease, in particular Alzheimer's disease, or determining the propensity or predisposition of a subject to develop such a disease by (i) detecting a level, or an activity, or both said level and said activity, of said transcription product and/or said translation product of a gene coding for golgin-245, in a sample from said subject;
- and (ii) diagnosing or prognosticating a neurodegenerative disease, in particular Alzheimer's disease, or determining the propensity or predisposition of said subject to develop such a disease, wherein a varied level, or activity, or both said level and said activity, of said transcription product and/or said translation product compared to a reference value representing a known health status;
- or a level, or activity, or both said level and said activity, of said transcription product and/or said translation product similar or equal to a reference value representing a known disease status indicates a diagnosis or prognosis of a neurodegenerative disease, in particular Alzheimer's disease, or an increased propensity or predisposition of developing such a disease.
A method of treating or preventing a neurodegenerative disease, in particular Alzheimer's disease, in a subject comprising administering to said subject in a therapeutically or prophylactically effective amount an agent or agents which directly or indirectly affect an activity and/or a level of
- (i) a gene coding for golgin-245, and/or
- (ii) a transcription product of a gene coding for golgin-245, and/or
- (iii) a translation product of a gene coding for golgin-245, and/or
- (iv) a fragment, or derivative, or variant of (i) to (iii).
A modulator of an activity and/or of a level of at least one substance which is selected from the group consisting of
- (i) a gene coding for golgin-245 and/or
- (ii) a transcription product of a gene coding for golgin-245 and/or
- (iii) a translation product of a gene coding for golgin-245, and/or
- (iv) a fragment, or derivative, or variant of (i) to (iii).
A recombinant, non-human animal comprising a non-native gene sequence coding for golgin-245 or a fragment, or a derivative, or a variant thereof, said animal being obtainable by:
- (i) providing a gene targeting construct comprising said gene sequence and a selectable marker sequence, and
- (ii) introducing said targeting construct into a stem cell of a non-human animal, and
- (iii) introducing said non-human animal stem cell into a non-human embryo, and
- (iv) transplanting said embryo into a pseudopregnant non-human animal, and
- (v) allowing said embryo to develop to term, and
- (vi) identifying a genetically altered non-human animal whose genome comprises a modification of said gene sequence in both alleles, and
- (vii) breeding the genetically altered non-human animal of step (vi) to obtain a genetically altered non-human animal whose genome comprises a modification of said endogenous gene, wherein said disruption results in said non-human animal exhibiting a predisposition to developing symptoms of a neurodegenerative disease or related diseases or disorders.
An assay for screening for a modulator of neurodegenerative diseases, in particular Alzheimer's disease, or related diseases or disorders of one or more substances selected from the group consisting of
- (i) a gene coding for golgin-245, and/or
- (ii) a transcription product of a gene coding for golgin-245, and/or
- (iii) a translation product of a gene coding for golgin-245, and/or
- (iv) a fragment, or derivative, or variant of (i) to (iii), said method comprising:
- (a) contacting a cell with a test compound;
- (b) measuring the activity and/or level of one or more substances recited in (i) to (iv);
- (c) measuring the activity and/or level of one or more substances recited in (i) to (iv) in a control cell not contacted with said test compound;
- and
- (d) comparing the levels and/or activities of the substance in the cells of step (b) and (c), wherein an alteration in the activity and/or level of substances in the contacted cells indicates that the test compound is a modulator of said diseases or disorders.
A method of screening for a modulator of neurodegenerative diseases, in particular Alzheimer's disease, or related diseases or disorders of one or more substances selected from the group consisting of
- (i) a gene coding for golgin-245, and/or
- (ii) a transcription product of a gene coding for golgin-245, and/or
- (iii) a translation product of a gene coding for golgin-245, and/or
- (i) a fragment, or derivative, or variant of (i) to (iii), said method comprising:
- (a) administering a test compound to a test animal which is predisposed to developing or has already developed symptoms of a neurodegenerative disease or related diseases or disorders in respect of the substances recited in (i) to (iv);
- (b) measuring the activity and/or level of one or more substances recited in (i) to (iv);
- (c) measuring the activity and/or level of one or more substances recited in (i) or (iv) in a matched control animal which is predisposed to developing or has already developed symptoms of a neurodegenerative disease or related diseases or disorders in respect to the substances recited in (i) to (iv) and to which animal no such test compound has been administered;
- (d) comparing the activity and/or level of the substance in the animals of step (b) and (c), wherein an alteration in the activity and/or level of substances in the test animal indicates that the test compound is a modulator of said diseases or disorders.
An assay for testing a compound, preferably for screening a plurality of compounds for inhibition of binding between a ligand and golgin-245 protein, or a fragment, or derivative, or variant thereof, said assay comprising the steps of:
- (i) adding a liquid suspension of said golgin-245 protein, or a fragment, or derivative, or variant thereof, to a plurality of containers;
- (ii) adding a compound or a plurality of compounds to be screened for said inhibition of binding to said plurality of containers;
- (iii) adding a detectable ligand, in particular a fluorescently detectable ligand, to said containers;
- (iv) incubating the liquid suspension of said golgin-245 protein, or said fragment, or derivative, or variant thereof, and said compound or compounds, and said ligand;
- (v) measuring amounts of detectable ligand or fluorescence associated with said golgin-245 protein, or with said fragment, or derivative, or variant thereof;
- and
- (vi) determining the degree of inhibition by one or more of said compounds of binding of said ligand to said golgin-245 protein, or said fragment, or derivative, or variant thereof.
An assay for testing a compound, preferably for screening a plurality of compounds, to determine the degree of binding of said compound or compounds to golgin-245 protein, or to a fragment, or derivative, or variant thereof, said assay comprising the steps of:
- (i) adding a liquid suspension of said golgin-245 protein, or a fragment, or derivative, or variant thereof, to a plurality of containers;
- (ii) adding a detectable compound, preferably a plurality of detectable compounds, in particular fluorescently detectable compounds, to be screened for said binding to said plurality of containers;
- (iii) incubating said liquid suspension of said golgin-245 protein, or said fragment, or derivative, or variant thereof, and said compound, preferably said plurality of compounds;
- (iv) measuring amounts of detectable compound or fluorescence associated with said golgin-245 protein, or with said fragment, or derivative, or variant thereof;
- and
- (v) determining the degree of binding by one or more of said compounds to said golgin-245 protein, or said fragment, or derivative, or variant thereof.
A protein molecule, said protein molecule being a translation product of the gene coding for golgin-245, SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, or SEQ ID NO. 8, or a fragment, or derivative, or variant thereof, for use as a diagnostic target for detecting a neurodegenerative disease, preferably Alzheimer's disease.
A protein molecule, said protein molecule being a translation product of the gene coding for golgin-245, SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, or SEQ ID NO. 8, or a fragment, or derivative, or variant thereof, for use as a screening target for reagents or compounds preventing, or treating, or ameliorating a neurodegenerative disease, preferably Alzheimer's disease.
Use of an antibody specifically immunoreactive with an immunogen, wherein said immunogen is a translation product of a gene coding for golgin-245, SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, or SEQ ID NO. 8, or a fragment, or derivative, or variant thereof, for detecting the pathological state of a cell in a sample from a subject, comprising immunocytochemical staining of said cell with said antibody, wherein an altered degree of staining, or an altered staining pattern in said cell compared to a cell representing a known health status indicates a pathological state of said cell.
Dependencies are inferred from the claim text.