The program for phenotyping of genetically modified animals at AstraZeneca

Area of Science:

• Preclinical drug discovery
• Genetically modified animal models
• Pharmacological research

Background:

• Genetically modified mice are valuable tools in preclinical drug discovery for target identification, validation, and disease modeling.
• Genomic modifications can lead to unforeseen phenotypic alterations beyond the intended genetic changes.
• Establishing comprehensive phenotypes is essential for the reliable use of these models in pharmaceutical research.

Purpose of the Study:

• To evaluate the importance of thorough phenotyping for transgenic and knockout mouse models.
• To assess the frequency and nature of unintended phenotypic alterations in genetically modified mice used for pharmaceutical research.

Main Methods:

• A cohort of 51 genetically modified mouse models (transgenic and knockout) was analyzed.
• A comprehensive phenotyping strategy was employed, including clinical and morphological assessments.
• Histopathological examinations were conducted to identify genotype-related changes.

Main Results:

• Phenotypic abnormalities were observed in 36 (70.6%) of the evaluated mouse models.
• The majority of observed abnormalities were minor in magnitude.
• Histopathological changes linked to the animals' genotype were identified in 33% of the models.

Conclusions:

• Comprehensive phenotyping is critical for genetically modified mouse models in drug discovery.
• A significant percentage of these models exhibit unintended phenotypic alterations, necessitating careful evaluation.
• Pathology plays a vital role in the phenotyping program for accurate assessment of genetically modified mice.