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Methods for treating apoe4/4-associated disorders

A technology for Alzheimer's disease, objects, applied in chemical instruments and methods, biochemical equipment and methods, pharmaceutical formulations, etc.

Pending Publication Date: 2021-02-12
THE J DAVID GLADSTONE INST A TESTAMENTARY TRUST ESTABLISHED UNDER THE WILL OF J DAVID GLADS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although AD is the leading cause of dementia worldwide, no effective treatment is yet available

Method used

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  • Methods for treating apoe4/4-associated disorders
  • Methods for treating apoe4/4-associated disorders
  • Methods for treating apoe4/4-associated disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 to 3

[0200] Data Integration. Search the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) and National Institute of Aging's Accelerating Drug Collaboration - Accelerating Alzheimer's Disease Transcriptome AD data from the Medicines Partnership-Alzheimer's Disease (AMP-AD) database from temporal lobe tissues for which apoE genotype information was available. From the NCBI GEO database in available series matrix file format 24 Direct download from Webster et al, 2009 17 Microarray experiments, accession number GSE15222. The data has been described as 17，25 Perform rank-invariant normalization. The prenormalization procedure created negative values ​​in the series matrix file, which can be eliminated by adding a constant to the expression matrix 26 . Since the fold change (FC) calculated after this addition was underestimated, all subsequent FC estimates were conservative with respect to the threshold. The Log2 transformation is then applied to...

Embodiment 4 to 6

[0218] Brain slice electrophysiological recording and data analysis. For long-term potentiation (LTP) recording studies, apoE4-KI mice were randomly assigned to vehicle (n=6, age 15.2±0.56 months) and bumetanide (n=3, age 15.1 ±0.06) treatment group. ApoE3-KI mice were similarly assigned to vehicle (n=6, age 15.5±0.11) and bumetanide (n=3, age 15.57±0.19) treated groups. For input / output recording studies, apoE4-KI mice were randomly assigned to vehicle (n=3, age 15.1±0.06 months) and bumetanide (n=3, age 15.1±0.06) treatments Group. ApoE3-KI mice were similarly assigned to vehicle (n=7, age 15.3±0.06) and bumetanide (n=3, age 15.57±0.29) treated groups. All mice were dosed for 6 to 8 weeks and slice recording days and dosing times were randomly assigned between groups to allow for equal dosing times while the experiments were performed. The final bumetanide injection was performed one hour before sacrifice. All mice were 16 to 17 months of age at the time of recording. ...

Embodiment 1

[0231] Computerized screening and identification of bumetanide

[0232] The study protocol is described and the results are shown here.

[0233] Described herein is an apoE genotype-specific drug repositioning method for screening drugs for the treatment of AD and / or diseases and disorders associated with the apoE4 / 4-genotype.

[0234] An apoE genotype-specific transcriptome signature of AD was established by gene expression meta-analysis of 610 human temporal lobe samples obtained from public databases and used to query a validated transcriptome perturbation signature comprising 1300 existing drugs The Connectivity Map (CMap) database was used to identify drugs that perturb entire gene expression networks away from apoE genotype-driven disease states toward normal states.

[0235] The ApoE genotype-specific transcriptome signature of AD from publicly available databases was first analyzed and the first CMap database search using the ApoE genotype-specific signature of AD w...

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Abstract

The present disclosure provides methods of treating Alzheimer's Disease (AD) and rescuing cognitive deficits associated with AD in a subject having an apoE4 / 4 genotype, by administering a therapeutically effective amount of the loop-diuretic bumetanide to the subject. Also disclosed are kits for performing the method, including one or more doses of a bumetanide formulation; and which may also include instructions for treating a patient having an apoE4 / 4 genotype by administering bumetanide, and / or instructions and reagents for testing / identifying a subject having an apoE4 / 4 genotype.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 656,898, filed April 12, 2018, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with Government support under Grant No. AG057683 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Alzheimer's Disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and is the most common form of dementia in the elderly. Genetic, pathological and functional studies have provided evidence that an imbalance between the production and clearance of amyloid-β (Aβ) peptides in the brain leads to the accumulation and aggregation of Aβ. Toxic Aβ aggregates in the form of soluble Aβ oligomers, and Aβ and amyloid plaques in neurons damage synapses and eventually cause neurodegenerati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61P25/28C07K14/775G01N33/68
CPCC07K14/775A61P25/28A61K9/0019A61K9/19A61K9/08A61K47/26A61K47/183C12Q2600/156C12Q1/6883A61K9/0053A61K9/7023A61K31/196C12Q2600/106
Inventor 黄亚东爱丽丝·陶贝斯菲尔·诺娃玛丽娜·西罗塔
Owner THE J DAVID GLADSTONE INST A TESTAMENTARY TRUST ESTABLISHED UNDER THE WILL OF J DAVID GLADS
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