Method of diagnosis, prognostic or treatment of neurodegenerative disease
Inventors
Papy-Garcia, Dulce • Huynh, Minh Bao • Soussi-Yanicostas, Nadia • Vozari, Rita • Sineriz, Fernando • Yanicostas, Constantin
Assignees
Centre National de la Recherche Scientifique CNRS • Assistance Publique Hopitaux de Paris APHP • Universite Paris Est Creteil Val de Marne • Sorbonne Universite • Institut du Cerveau et de La Moelle Epiniere ICM • Organes Tissus Regeneration Reparation Remplacement SAS
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Publication Number
US-10324096-B2
Publication Date
2019-06-18
Expiration Date
Abstract
Methods for the diagnosis and prognosis of neurodegenerative diseases, such as Alzheimer's disease, are described. Compositions and method for the treatment of neurodegenerative diseases are also described.
Core Innovation
The invention relates to diagnostic/prognostic and therapeutic strategies for neurodegenerative disease, with emphasis on Alzheimer’s disease and Tauopathy, centered on 3-OST-2 and/or 3-OST-4 (HS3ST2/HS3ST4). It links altered activity and/or level of 3-OST-2/-4 to the presence of 3-O-sulfated heparan sulfate and to Tau abnormalities, including 3-O-sulfated heparan sulfate species that bind Tau and abnormal Tau phosphorylation together with total Tau.
The document describes a need to detect and distinguish Tauopathy states in subjects, including differentiating sporadic Alzheimer’s disease from other Tauopathies. It uses biological fluids such as CSF, plasma, and blood and emphasizes identifying molecular markers associated with 3-O-sulfated heparan sulfate, including 3-O-sulfated heparan sulfate disaccharides such as TriS and TetraS.
The invention relates to an in vitro screening method for a modulator of the activity and/or level of a molecule selected from gene, transcription, translation product, a fragment or derivative, heparan sulfate, or Tau protein in a subject being subject to a Tauopathy, provided that the Tauopathy is different from a prion disease. The method includes contacting a sample of a biological fluid collected from the subject with a test compound and determining the activity and/or level of the selected molecule in the contacted sample compared with a control sample from a subject with a Tauopathy that is not contacted with the test compound, where an alteration indicates modulation.
The screening method is grounded on measuring heparan sulfate that is 3-O-sulfated and specifically associated with Tau protein abnormalities, including abnormally phosphorylated Tau protein and/or total Tau protein. It links marker determination to gene/transcription/translation products for an heparin-glucosamine 3-O-sulfotransferase selected from nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 3 and translation products set forth by SEQ ID NO: 2 and SEQ ID NO: 4.
Claims Coverage
The independent claim covers an in vitro screening workflow for a test compound that modulates the activity and/or level of at least one selected molecule from a defined group of gene-related products, heparan sulfate, or Tau protein, based on comparison between contacted and non-contacted biological fluid samples, while excluding prion disease. Dependent claims refine the subject context and measurement to Alzheimer’s disease and to 3-O-sulfated heparan sulfate disaccharide-corresponding levels.
In vitro screening of a test compound on selected gene/heparan sulfate/Tau molecules in Tauopathy biological fluid
A method for an in vitro screening in which a sample of a biological fluid collected from a subject being subject to a Tauopathy, different from a prion disease, is contacted with a test compound, followed by determining the activity and/or level of at least one molecule selected from a gene, a transcription of a gene, a translation product of a gene, a fragment or derivative of these, heparan sulfate, or a Tau protein, wherein the contacted sample determination is compared with the determination in a control sample not contacted with the test compound, and wherein an alteration indicates that the test compound is a modulator of the selected molecule(s).
Excluding prion disease from the Tauopathy screening condition
The screening method requires that the Tauopathy for the biological fluid sample is different from a prion disease.
Determining 3-O-sulfated heparan sulfate and abnormally phosphorylated Tau or total Tau
The method provides that the activity and/or level can be determined for 3-O-sulfated heparan sulfate and for abnormally phosphorylated Tau protein and/or total Tau protein as the selected molecules to indicate modulation by the test compound.
Control comparison between contacted and non-contacted Tauopathy biological fluid samples
The activity and/or level determined in the contacted biological fluid sample with the test compound is compared with the activity and/or level determined in a non-contacted biological fluid control sample collected from a subject with a Tauopathy.
Subject/model refinement for the Tauopathy screening context
The method of the independent claim is performed with a subject that is specified as a mammal, human, mouse, SAMP8 mouse, 3xTg-AD mouse model of Alzheimer’s disease, or zebrafish.
Narrowing Tauopathy to Alzheimer’s disease
The Tauopathy in the method is Alzheimer’s disease.
Linking 3-O-sulfated heparan sulfate level to a corresponding 3-O-sulfated heparan sulfate disaccharide level
The measured level of 3-O-sulfated heparan sulfate corresponds to the level of the 3-O-sulfated heparan sulfate disaccharide.
SEQ sequence-defined heparin-glucosamine 3-O-sulfotransferase marker set
Determining activity and/or level for gene and transcription using nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 3 and coding for an heparin-glucosamine 3-O-sulfotransferase, and determining activity and/or level for translation products set forth respectively by SEQ ID NO: 2 and SEQ ID NO: 4.
Overall, the claim set covers an in vitro screening method that tests compounds for modulation of a defined set of molecules in Tauopathy biological fluid, excluding prion disease, with measurement options spanning gene, transcription, and translation products tied to heparin-glucosamine 3-O-sulfotransferase, 3-O-sulfated heparan sulfate, and abnormally phosphorylated Tau and/or total Tau. Dependent claims further narrow the subject or model context and specify Alzheimer’s disease and measurement of 3-O-sulfated heparan sulfate via a corresponding disaccharide level.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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