Academy

Mosaic Genetic Screening

Definition and Overview: Mosaic genetic screening is an advanced in vivo technique that introduces a pooled library of gene therapies into a single animal model. Each cell within the animal may receive a different genetic perturbation, resulting in a mosaic of cellular modifications that can be assessed simultaneously.

How It Works:

1. Preparation of Gene Therapy Library: Scientists assemble a diverse pool of viral vectors, each carrying a distinct gene therapy payload targeting specific genes or pathways.
2. Animal Model Selection: Researchers choose a ‘patient avatar’—an animal that naturally develops a human-like disease phenotype (e.g., horses with osteoarthritis or primates with metabolic steatohepatitis).
3. Administration and Expression: The gene therapy library is delivered systemically or locally to the animal, where each vector infects a subset of cells, creating a mosaic of genetic interventions.
4. Tissue Sampling and Analysis: After a defined period, tissues are harvested and analyzed using sequencing and imaging to quantify the performance of each gene therapy based on disease-relevant readouts.

Advantages in Longevity Research:

• Physiological Relevance: Maintains whole-body context, including immune responses, metabolism and cellular interactions, which are critical for aging-related diseases.
• High Throughput: Screens hundreds to thousands of interventions in parallel, drastically improving efficiency over sequential ex vivo assays.
• Predictive Accuracy: Demonstrates higher concordance with clinical outcomes by testing directly in disease-bearing animals.

Applications: Mosaic genetic screening accelerates target discovery for chronic conditions that define aging—such as osteoarthritis, heart failure with preserved ejection fraction (HFpEF), obesity and pulmonary fibrosis. It is modality-agnostic, enabling follow-up development as gene therapies, proteins or small molecules.

Limitations and Considerations: Viral vector delivery and immune reactions must be carefully managed. Model selection is critical to ensure translational relevance. Ethical and regulatory frameworks for animal use must be strictly followed.

Future Directions: Integration with more sophisticated AI analytics and expansion to additional models (e.g., nonhuman primates) will further enhance predictive power. Combining mosaic screening with longitudinal imaging and single-cell omics promises deeper insights into aging mechanisms and therapeutic interventions.