Composite Genetically Modified Mice for Late-Onset Alzheimer’s Modeling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The lack of suitable animal models for preclinical trials of late-onset Alzheimer's disease, which accounts for 95-98% of the human population, as existing models are based on familial mutations and do not accurately represent the multifactorial nature of late-onset Alzheimer's disease.
Innovation Solution
Development of genetically modified mice incorporating human APOE4, mouse TREM2 with a R47H substitution, and additional genomic modifications such as humanized ABCA7, APP, PLCG2, MTHFR, inactivated Ceacaml, and IL1RAP alleles, to mimic late-onset Alzheimer's disease pathologies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse models based on familial mutations are used, then treatment effectiveness can be demonstrated in early-onset Alzheimer's disease, but the models do not accurately represent late-onset Alzheimer's disease pathologies
Solution Approach 1:
The patent applies parameter changes by modifying multiple genetic parameters simultaneously in the mouse model. Instead of using simple familial mutation models, the invention incorporates human APOE4 allele, mouse TREM2 R47H substitution, and additional humanized mutations (ABCA7 A1541G, APP G601R/F606Y/R609H, PLCG2 M28L, MTHFR A262V) to create a composite genetic profile that accurately reflects the multifactorial nature of late-onset Alzheimer's disease in humans.
Solution Approach 2:
The patent creates a composite genetic system by combining multiple different genetic elements and mutations into a single mouse model organism. This composite approach integrates human and mouse genetic sequences, multiple risk alleles, and gene knockouts to produce a model that captures the complexity of late-onset Alzheimer's disease, enabling more accurate preclinical trial predictions.
2Reliability
If multiple genomic modifications are introduced to create accurate late-onset Alzheimer's disease models, then disease representation accuracy improves, but model complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the complex genetic modification process into manageable components. Each genomic modification (APOE4, TREM2 R47H, ABCA7 A1541G, APP mutations, PLCG2 M28L, MTHFR A262V, Ceacaml KO, IL1RAP KO) represents a separate genetic element that can be independently introduced and characterized. This modular approach allows systematic assembly of the complete model while maintaining trackability of each component's contribution.
Data Source
AI summary
The present disclosure provides a genetically modified mouse comprising a genomic nucleic acid encoding human APOE4, a genomic nucleic acid encoding mouse TREM2 modified to include a R47H substitution, and at least one genomic modification selected from the group consisting of: (a) a genomic nucleic acid encoding mouse ABCA7 modified to include an A 1541 G substitution; (b) a genomic nucleic acid encoding mouse APP modified to include G60IR, F606Y, and R609H substitutions; (c) a genomic nucleic acid encoding mouse PLCG2 modified to include a M28L substitution; (d) a genomic nucleic acid encoding mouse MTHFR modified to include a A262V substitution; (e) an inactivated Ceacaml allele; and (f) an inactivated II1rap allele. Methods of producing the genetically modified mouse and methods of using the genetically modified mouse are also provided.