CRISPR RNA Therapy and Lung Chip Offer Preclinical Promise for Pan-Influenza A Nanotherapeutics

A persistent threat looms over global health: the Influenza A virus (IAV). Responsible for six major flu pandemics, IAV has caused staggering historical mortality and continues to drive high seasonal hospitalization and death rates, even with updated vaccines. The fundamental challenge in creating durable treatments lies in IAV’s relentless ability to mutate and rearrange its genetic material, rendering many antiviral drugs quickly obsolete and posing a constant risk for new pandemic strains to emerge.

For decades, the search for an effective, broad-acting weapon has been stifled by the reliance on animal models, such as mice and ferrets, which fail to accurately mimic human anatomy, immune responses, and drug delivery requirements in the lung. The sequences targeted by cutting-edge CRISPR technology are often so human-specific that meaningful studies could not be carried out in these traditional preclinical settings.

However, a groundbreaking collaborative study from the Wyss Institute at Harvard University has successfully bypassed these limitations by uniting advanced CRISPR RNA Therapy with human Lung Chip technology.

The Wyss team, led by Founding Director Donald Ingber and Associate Director Natalie Artzi, leveraged a microfluidic human lung alveolus chip—a model that mimics the lung's tiny air sacs and their natural "breathing" motion. This Lung Chip provides a highly relevant human preclinical testbed, enabling efficacy and safety evaluation in a way earlier approaches could not.

The key to their success lay in designing a CRISPR RNA Therapy that targets two invariable, strongly conserved regions in the IAV genome’s polymerase basic 1 (PB1) gene—sequences found across the vast majority of human-infecting IAV viruses. This design makes the treatment broadly effective, or Pan-Influenza A.

Crucially, the team faced the challenge of delivery. To protect the therapeutic RNA molecules (crRNAs and the Cas13 enzyme mRNA) and ensure they reached the epithelial cells lining the lung chip, they packaged them into tiny nanoparticles. This sophisticated platform, known as nanotherapeutics, successfully delivered the load efficiently to the lung epithelial cells.

The results demonstrated potent activity: a single administration of the CRISPR nanotherapeutics to the infected Lung Chip reduced the viral load by over 50%. Furthermore, the treatment significantly blunted the host inflammatory response caused by the virus. Transcriptomic analysis confirmed the system incurred only minimal off-target effects on the human lung cells.

These findings establish the human Lung Chip as an unprecedented preclinical tool for developing and assessing new antiviral drugs. Given the high likelihood of future pandemics and continuous seasonal variation, developing Pan-Influenza A antiviral treatments like this CRISPR RNA Therapy could be instrumental in helping medicine get "ahead of the virus" and saving thousands of lives. The development of such durable treatments marks a significant step forward in preparing for future respiratory health crises.

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🔖 Sources

CRISPR therapy shows promise against influenza in human lung chips

Human Organ Chip technology sets stage for pan-influenza A CRISPR RNA therapies

Human organ chip technology sets stage for pan-influenza A CRISPR RNA therapies

Human Organ Chip Technology Paves the Way for Pan-Influenza A CRISPR RNA Therapies

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