Dynactin subunit p62 biomarker for neurological conditions
Inventors
Kirsch, Wolff M. • Schrag, Matthew • Crofton, Andrew • Zabel, Matthew • Mueller, Claudius
Assignees
Publication Number
US-9746458-B2
Publication Date
2017-08-29
Expiration Date
2032-04-26
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Abstract
Methods and kits for identifying neurological conditions in a patient by determining a level of expression of dynactin subunit p62 are disclosed. The neurological conditions may include, for example, Alzheimer's Disease (AD) without cerebral amyloid angiopathy (CAA).
Core Innovation
The invention provides methods and kits for diagnosing neurological conditions, particularly Alzheimer's Disease (AD) without cerebral amyloid angiopathy (CAA), by determining the expression level of dynactin subunit p62 in biological samples from patients. The invention also includes kits that utilize antibodies specific to dynactin subunit p62, substrates such as microtiter plates or microcolumns, and reference samples that distinguish between AD with and without CAA based on dynactin subunit p62 expression levels in plasma.
The background indicates that reliable and noninvasive methods for early diagnosis of AD are not available, and no clinically validated serum biomarkers exist for early detection or confirmation of AD, especially at the stage of mild cognitive impairment (MCI). The invention addresses this problem by identifying altered levels of dynactin subunit p62 as a biomarker for AD, providing a basis for diagnosis and disease sub-grouping. The invention further outlines detection methods such as immunoassays, mass spectrometry, and antibody-based techniques applied to blood, serum, or plasma samples.
In addition to diagnostic utility, the invention covers methods for screening therapeutic agents by evaluating the modulation of dynactin p62 levels (and synaptic vesicle copper) as a readout, both in vivo and in vitro. The approaches include use of neuronal cells and animal models with disrupted dynactin p62 function to model AD, enabling the identification of compounds that normalize or increase dynactin p62 levels as potentially beneficial agents for AD therapy or prophylaxis.
Claims Coverage
The patent contains three independent kit-related claims, each outlining a kit for detecting Alzheimer's Disease without cerebral amyloid angiopathy in a human subject, with several specific inventive features.
Kit with substrate, antibody, controls, and instructions for AD without CAA
A kit for detecting Alzheimer's Disease (AD) without cerebral amyloid angiopathy (CAA) in a human subject comprising: - A substrate selected from the group consisting of a microtiter plate and a microcolumn. - An antibody that specifically detects a dynactin subunit p62 polypeptide, wherein the antibody is bound to the substrate. - A negative reference sample indicative of a subject having AD and CAA. - A positive control indicative of a subject having AD without CAA, where this positive control shows an increased level in plasma of dynactin subunit p62 versus the negative sample. - Instructions for determining the level of dynactin subunit p62 expression and classifying the subject based on whether this level is greater than a predetermined value corresponding to the negative reference sample.
Kit with substrate, antibody, negative and positive controls for AD without CAA
A kit for detecting Alzheimer's Disease without cerebral amyloid angiopathy in a human subject comprising: - A substrate chosen from a microtiter plate or microcolumn. - An antibody that specifically detects dynactin subunit p62, bound to the substrate. - A negative reference sample indicative of AD with CAA. - A positive control indicative of AD without CAA, where the positive control demonstrates increased dynactin subunit p62 in plasma relative to the negative control.
Kit with substrate, antibody, and positive reference control for AD without CAA
A kit for detecting Alzheimer's Disease without cerebral amyloid angiopathy in a human subject comprising: - A substrate (microtiter plate or microcolumn). - An antibody specifically for dynactin subunit p62, bound to the substrate. - A positive reference control indicative of a human subject with increased likelihood of having or developing AD without CAA, evidenced by increased plasma dynactin subunit p62 compared to a subject with AD and CAA.
The independent claims focus on kits designed to diagnose AD without CAA by measuring plasma dynactin subunit p62 with specific substrates, antibodies, and reference controls enabling the differential classification of AD subtypes.
Stated Advantages
The methods provide a reliable and noninvasive approach for diagnosing Alzheimer's Disease and distinguishing AD without cerebral amyloid angiopathy.
Detection using plasma, blood, or serum allows for early diagnosis, including during mild cognitive impairment stages, improving the chances for treatment and future planning.
The invention enables monitoring the progression and severity of neurological conditions through biomarker levels.
Kits allow for the classification of AD subgroups, such as distinguishing AD with and without CAA, which supports more precise diagnosis and potential treatment strategies.
Screening methods for therapeutic agents based on changes in dynactin p62 levels facilitate the identification of potential treatments for AD.
Documented Applications
Diagnosis and classification of Alzheimer's Disease without cerebral amyloid angiopathy in human patients by measuring dynactin subunit p62 levels.
Screening candidate therapeutics for Alzheimer’s Disease by assessing their effects on dynactin p62 and synaptic vesicle copper levels in vivo and in vitro.
Use as a prognostic or monitoring tool for neurological conditions, including Alzheimer’s Disease, mild cognitive impairment, vascular dementia, cerebral amyloid angiopathy, brain microhemorrhages, and related subgroups.
Development of animal and cellular models with disrupted dynactin p62 expression for studying Alzheimer’s Disease pathogenesis and for therapeutic screening.
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