Genetically Modified Alzheimer’s Mouse Model for Late-Onset AD Screening
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Solution Overview
Problem
The lack of effective animal models for preclinical trials of late-onset Alzheimer's disease, which accounts for 95-98% of the human population, due to the complexity of its genetic and environmental causes, hinders the development of therapies.
Innovation Solution
Development of a genetically modified mouse model incorporating human APOE4, mouse TREM2 with a R47H substitution, and humanized mutant mouse APP with G601R, F606Y, and R609H substitutions to mimic late-onset Alzheimer's disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If familial Alzheimer's disease mouse models are used, then the models have simple and defined genetic etiology, but they do not represent the vast majority of clinical population with non-familial late-onset AD
Solution Approach 1:
The patent applies local quality by selectively introducing specific human genetic variants (APOE4, APP Swedish mutation, TREM2 R47H) into the mouse genome at specific loci. This allows the model to capture the local genetic risk factors associated with late-onset AD while maintaining the overall mouse genetic background, thereby achieving both genetic definition and clinical representativeness.
Solution Approach 2:
The patent creates a composite genetic model by combining multiple human genetic elements (human APOE4 allele, human APP mutation, human TREM2 variant) within a single mouse organism. This composite approach allows the model to represent the multifactorial nature of late-onset AD, which arises from interactions between multiple genetic and environmental factors.
2Reliability
If late-onset Alzheimer's disease is modeled with multiple genetic and environmental factors, then the model represents the clinical population better, but the genetic etiology becomes complex and difficult to define
Solution Approach 1:
The patent segments the complex etiology of late-onset AD into discrete, manageable genetic components: the APOE4 allele, the APP Swedish mutation, and the TREM2 R47H variant. By dividing the multifactorial disease into these specific segments, the model maintains clinical representativeness while allowing for controlled genetic analysis.
Solution Approach 2:
The patent changes key genetic parameters by introducing specific human alleles and mutations into the mouse genome. This allows the model to capture the essential pathogenic features of late-onset AD (apolipoprotein E4 risk, amyloid-beta production, microglial dysfunction) while maintaining a defined and controllable genetic system.
3Productivity
If treatments are tested in familial Alzheimer's disease mouse models, then the trials can be conducted, but the treatments are not effective when tested in clinical trials
Solution Approach 1:
The patent creates a more accurate copy of the human late-onset AD condition by incorporating multiple human genetic risk factors (APOE4, APP Swedish mutation, TREM2 R47H) into the mouse model. This improved copying ensures that preclinical trial results are more predictive of clinical trial outcomes, thereby increasing translational success rate while maintaining reasonable productivity.
Data Source
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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 G601R, 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 ΙĮ1rap allele. Methods of producing the genetically modified mouse and methods of using the genetically modified mouse are also provided.