How animal models from mice to macaques are advancing the NIH Somatic Cell Genome Editing Program and revolutionizing gene therapies
In research labs across the country, a quiet revolution is underway—one that bridges species from the humble mouse to the sophisticated macaque in a daring quest to rewrite the code of life.
These animal counterparts, each playing a distinct role in the intricate ballet of biomedical research, form the backbone of the National Institutes of Health's Somatic Cell Genome Editing (SCGE) Program, an ambitious six-year, $190 million initiative launched to accelerate the development of safer genome editing therapies 1 .
The program's vision is both simple and profound: to create a comprehensive toolkit that allows scientists to precisely edit the genomes of disease-relevant cells in patients, even in tissues that have long been considered difficult to reach 1 . By moving from "reading" to "writing" the human genome, researchers hope to unlock new treatments for a vast spectrum of conditions that have stubbornly resisted conventional approaches.
Targeted modifications to correct genetic defects
Multiple species providing essential biological insights
Potential treatments for previously untreatable conditions
Medical research traditionally follows a stepped approach, and genome editing is no exception. Each animal model brings distinct advantages to the research process, creating a complementary cascade of biological insights:
Advantages:
Limitations:
Advantages:
Limitations:
This stepped approach allows researchers to answer fundamentally different questions at each stage: "Can we make this edit?" (often answered in mice), "Does the edit produce the intended physiological effect?" (better assessed in larger animals), and "Is this approach safe enough for human trials?" (ideally answered in non-human primates) 1 .
Initial testing in cell cultures to validate editing approaches and assess efficiency.
Proof-of-concept studies to demonstrate feasibility and initial safety assessment.
Assessment of physiological effects, dosage optimization, and more comprehensive safety evaluation.
Final preclinical testing to predict human responses and identify potential immune reactions.
Translation to patients after successful preclinical validation.
In 2021, a landmark study published in Nature Biotechnology demonstrated the power of this animal cascade approach, culminating in a sophisticated experiment that targeted the PCSK9 gene in macaques—a gene that regulates LDL cholesterol levels in the blood 5 .
The research team employed a sophisticated "hit-and-run" strategy designed to minimize risks associated with prolonged editor exposure:
Function: Regulates LDL cholesterol levels in the blood
Therapeutic Target: Reducing PCSK9 activity can lower cholesterol and cardiovascular risk
Editing Approach: Base editing to disrupt protein function
The outcomes of this carefully designed experiment were compelling, demonstrating both the promise and the current limitations of in vivo genome editing:
| Parameter | Results in Mice | Results in Macaques | Clinical Significance |
|---|---|---|---|
| Editing Efficiency | Up to 67% | Up to 34% | Demonstrates cross-species feasibility |
| PCSK9 Reduction | 95% | 32% | Indicator of target engagement |
| LDL Reduction | 58% | 14% | Relevant physiological outcome |
| Off-target Effects | None detected | None detected | Important safety indicator |
| Immune Response | None detected | Anti-Cas9 antibodies detected | Highlights species differences |
Without the macaque data, the critical limitation of immune response against Cas9 might have gone undiscovered until human trials, demonstrating the essential role of non-human primate models in the development of genome editing therapies 5 .
The success of genome editing experiments depends on a sophisticated array of molecular tools and delivery technologies. These core components work in concert to enable precise genetic modifications across different animal models:
Examples: CRISPR-Cas9, Base Editors, Prime Editors
Function: Create targeted DNA changes with varying precision
Applications: CRISPR-Cas9 for knockouts; Base editors for single-letter changes
Examples: Lipid Nanoparticles (LNPs), AAV Vectors
Function: Ferry editing machinery into target cells
Applications: LNPs for liver delivery; AAVs for retinal and brain delivery
Examples: crRNA:tracrRNA complexes, sgRNAs
Function: Direct editing machinery to specific genomic addresses
Applications: Species-specific designs for mouse, macaque, or human targets
Examples: Genome Editing Detection Kits, Sequencing
Function: Confirm editing efficiency and identify off-target effects
Applications: Quality control across animal models
These tools have been systematically optimized through the SCGE Consortium, which has brought together 72 principal investigators from 38 institutions to work on 45 integrated projects 1 . The consortium's rigorous approach requires validation of technologies through third-party testing in both small and large animals, ensuring that methods are properly benchmarked before advancing toward clinical applications.
A team from the University of Maryland recently won an NIH TARGETED Challenge prize for developing a technique that combines engineered nanoparticles, microbubbles, and focused ultrasound to deliver CRISPR components across the blood-brain barrier 8 .
Potential applications: Huntington's disease, genetic epilepsies, and glioblastoma 8 .
Researchers have used adeno-associated viruses (AAVs) to deliver CRISPR machinery to photoreceptor cells in both mice and macaques, demonstrating the viability of this approach for treating inherited retinal diseases 9 .
Advantage: The eye's contained environment makes it particularly suitable for localized therapies.
The first FDA-approved CRISPR therapy, Casgevy, for sickle cell disease and transfusion-dependent beta thalassemia, uses ex vivo editing—where cells are removed, edited in the laboratory, and then returned to the patient 4 .
Consideration: This approach bypasses some delivery challenges but is logistically complex and expensive.
The systematic progression from mouse to macaque studies continues to yield promising results that are gradually transitioning into human applications. Recent clinical developments highlight this encouraging trajectory:
In May 2025, researchers reported the first successful personalized CRISPR treatment for an infant with carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare and potentially fatal genetic liver disease 2 .
The therapy, which corrected a specific gene mutation in the baby's liver cells, was developed and delivered in just six months—demonstrating how platform technologies validated in animal models can accelerate bespoke treatments 2 4 .
Early results from clinical trials for hereditary transthyretin amyloidosis (hATTR) have shown that CRISPR therapies can produce quick, deep, and long-lasting reductions in disease-related proteins—with participants maintaining approximately 90% reduction in TTR protein levels over two years of follow-up 4 .
Delivery to many tissues beyond the liver and eyes remains inefficient 4 .
Funding fluctuations threaten continued progress 4 .
High costs of therapies create accessibility concerns 4 .
Strategies needed to mitigate immune responses against bacterial-derived editing proteins 5 .
"As a platform, gene editing—built on reusable components and rapid customization—promises a new era of precision medicine for hundreds of rare diseases."
— Dr. Kiran Musunuru, Geneticist 2
The journey from mouse to macaque—and ultimately to human patients—represents both a scientific and ethical progression. Each animal model plays a crucial role in minimizing risks while maximizing insights, ensuring that potential therapies are thoroughly vetted before reaching clinical trials.
This vision of a future where genetic conditions can be rapidly addressed with customized therapies depends fundamentally on the continued careful, systematic work across animal models.
The SCGE Consortium's work, and the animal allies that make it possible, are paving the way toward this future—one where reading our genetic destiny is just the first step toward writing a healthier one 1 .