From farm to lab: gene-edited sheep transforming bone research

Area of Science:

• Biomedical Research
• Translational Science
• Genetics

Background:

• Mice are traditional models in biomedical research due to their size, reproduction, and genetics.
• Genome editing has created mouse models for various human diseases, advancing biological understanding.
• However, significant physiological and skeletal differences between mice and humans limit their translatability, especially in musculoskeletal research.

Purpose of the Study:

• To highlight the limitations of mouse models in accurately recapitulating human skeletal biology.
• To introduce gene-edited large-animal models as a more translatable alternative for musculoskeletal research.
• To emphasize the potential of large-animal models in bridging the gap between basic research and clinical applications.

Main Methods:

• Reviewing the limitations of mouse models in musculoskeletal research, focusing on skeletal differences.
• Exploring advancements in genome sequencing, assembly, and molecular engineering for large-animal model development.
• Describing the application of targeted DNA editing in species like sheep, goats, and pigs.
• Detailing the potential for longitudinal, clinically-relevant phenotyping in large-animal models.

Main Results:

• Human and mouse skeletal biology, including bone remodeling and craniofacial development, exhibit critical differences.
• Large domesticated animals (sheep, goats, pigs) possess skeletal characteristics more closely mirroring humans.
• Gene-edited large-animal models can replicate human disease mechanisms and support translatable phenotyping.
• These models offer enhanced validation of disease pathways, biomarkers, and therapeutic interventions.

Conclusions:

• Gene-edited large-animal models provide a valuable complementary strategy to mouse models for human skeletal research.
• These models can improve the translatability of preclinical findings to clinical settings.
• Expanding the use of large-animal models will accelerate the development of effective treatments for human bone disorders.