CRISPR-Generated AAT Deficient Mouse Model for Lung Disease Screening

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current animal models for alpha-1 antitrypsin (AAT) deficiency-related lung disease are lacking, hindering the development of therapeutics due to the genomic complexity of mice and the embryonic lethality of traditional Serpina1 gene knockout approaches, which limits the availability of a viable and physiologically relevant model for human-like AAT-deficiency lung conditions.

Innovation Solution

Generation of transgenic mice with homozygous or heterozygous inactivating mutations in Serpina1 genes using CRISPR/Cas9 technology, resulting in animals that lack hepatic and circulatory AAT protein, mimicking human AAT-deficiency lung disease and allowing for the development of novel therapeutics.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional Serpina1 gene knockout approaches are used, then complete AAT deficiency is achieved, but embryonic lethality occurs

Engineering Contradiction:

ImproveAAT deficiency model reliabilityVSAvoidanimal survival duration

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent applies partial knockout strategy where only one allele of the Serpina1 gene is inactivated (heterozygous knockout) rather than complete biallelic knockout. This partial action achieves sufficient AAT deficiency phenotype for modeling human disease while avoiding the embryonic lethality caused by complete gene elimination, thus resolving the contradiction between model reliability and animal survival.

Inventive Principle:

Principle #16Partial or excessive action

2Adaptability or versatility

If complete Serpina1 gene knockout is performed, then human-like AAT deficiency is achieved, but genomic complexity prevents viable model creation

Engineering Contradiction:

Improvedisease model applicabilityVSAvoidgenomic manipulation complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent extracts and eliminates the problematic complexity by using targeted allele-specific knockout technology that focuses on inactivating only the disease-causing allele rather than attempting to eliminate all Serpina1 gene functions. This extraction approach isolates the essential disease-modeling function while removing the genomic complexity barrier, enabling creation of viable AAT-deficient mouse models that recapitulate human disease.

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS10822618B2Method of using a transgenic mouse with alpha-one antitrypsin (ATT) deficiency to screen compounds

Publication Date: 2020.11.03 UNIV OF MASSACHUSETTS

AI summary

Transgenic non-human animals, e.g., rodents, e.g., mice comprising genomic mutations that inactive all of the serpin1A genes and thus lack any functional serpinA1 genes. As a result of the genomic mutations, the animals express no hepatic or circulatory AAT protein. Also provided herein are cells and tissues derived from the transgenic mice.