APP-Specific CD8+ T Cell Assay for LOAD Diagnosis

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Solution Overview

Problem

Current mouse models for late-onset Alzheimer's disease (LOAD) are inadequate in mimicking human age-related factors, leading to incomplete replication of AD pathology, and there is a lack of effective diagnostic assays and therapeutic methods for identifying and treating LOAD.

Innovation Solution

A diagnostic assay that measures the level of APP-specific CD8+ T cells in a subject's sample using MHC multimers labeled with detection agents, such as fluorescent tags, and a therapeutic method involving APP peptide-specific MEW multimers conjugated to cytotoxic agents to treat subjects with increased likelihood of LOAD.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If FAD-based mouse models are used to study AD, then genetic mutations can be introduced, but they fail to replicate age-related factors and complete AD pathology

Engineering Contradiction:

Improvereplication of AD pathologyVSAvoidmimicking human age-related factors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent combines FAD-based genetic mutations with induced CD8 T cell homeostatic expansion in mouse models to create a more comprehensive AD pathology model. This merging of genetic and immune system manipulations allows the model to replicate both the genetic predisposition and age-related immune changes that occur in human AD, thereby improving the reliability of pathology replication while maintaining the ability to study specific genetic mechanisms.

Inventive Principle:

Principle #5Merging (Combining)

2Measurement precision

If CD8 T cell homeostatic expansion is induced in young hosts, then T cell clonal expansion occurs, but it is unclear if this corresponds to age-related clonal expansion in aging humans

Engineering Contradiction:

Improvecorrespondence to age-related clonal expansionVSAvoidinformation on age-related physiological processes

Core Design Contradiction:

Measurement precisionVSLoss of information

Solution Approach 1:

The patent uses induced CD8 T cell homeostatic expansion in young T cell-deficient hosts as an intermediary model to study age-related clonal expansion. By inducing this expansion in controlled young hosts, the model serves as an intermediary that can be manipulated and measured, providing insights into age-related processes without requiring actual aging, thus maintaining measurement precision while avoiding the complexity of studying real aging physiology.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If diagnostic assays for LOAD are developed, then identification of at-risk subjects is possible, but no effective assays currently exist

Engineering Contradiction:

Improveidentification of LOAD subjectsVSAvoiddevelopment of diagnostic assay

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent replaces complex mechanical and biochemical diagnostic systems with a simpler flow cytometry-based assay that detects CD8 T cells expressing specific surface markers (such as KLRG1, NKG2D, or TCR Vβ segments) indicative of APP-specific reactivity. This substitution of complex diagnostic machinery with a more straightforward immunophenotypic detection method improves reliability of LOAD identification while significantly easing the manufacturing and implementation of the diagnostic test.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS11567078B2Blood cell biomarker for late onset Alzheimer's disease

Publication Date: 2023.01.31 CEDARS SINAI MEDICAL CENT

AI summary

Described herein are compositions and methods for diagnosing late-onset Alzheimer's disease (LOAD), treating LOAD and assessing efficacy of therapeutic agents used to treat LOAD.