The promise of adeno-associated virus (AAV) vector-based gene therapies is undeniable. These therapies have already demonstrated potential in treating conditions like spinal muscular atrophy, retinal dystrophy, and hemophilia B, with the FDA approving three treatments as of early 2023. Yet, despite these successes, many promising therapies fail during clinical trials.
A recent article by Sara Donnelly on DDW Online explores why these failures often occur and highlights a critical solution: choosing the right preclinical models. The disconnect between preclinical studies and human clinical trials is a major obstacle, largely because traditional animal models, like non-human primates (NHPs) and conventional mouse models, often fall short in predicting human responses or are challenging to source.
The Limitations of Traditional Models
While NHPs share physiological similarities with humans, they struggle to predict AAV transduction efficiency in the human liver. These models are also expensive and come with ethical challenges. Furthermore, NHPs are larger species and require manufacturing of more test material to complete experiments. Meanwhile, standard mouse models, though widely used and cost-effective, lack human-specific genetic and metabolic features, leading to discrepancies in data on safety and efficacy.
A Better Alternative: Humanized Liver Mouse Models
Humanized liver mouse models, such as the PXB-mouse, are emerging as a game-changer in preclinical research. By engrafting these mice with human hepatocytes, researchers can mimic human liver physiology with remarkable accuracy. These models provide:
- Human gene and protein expression
- Improved predictability of AAV transduction and toxicity
- Streamlined and cost-effective integration into existing research setups
Why This Matters
Using more predictive models, like humanized liver mice, can drastically improve the success rate of AAV therapies progressing to clinical trials. These models help developers focus resources on the most promising candidates, potentially saving time, reducing costs, and bringing transformative treatments to patients faster.
To dive deeper into how humanized liver mouse models are revolutionizing gene therapy research, read the full article on DDW Online here.