Influenza A virus (IAV) has fueled six major pandemics, causing between 50 and 100 million deaths worldwide. In the United States, seasonal vaccines still leave IAV infections responsible for roughly 140,000 to 710,000 hospitalizations and 12,000 to 52,000 deaths each year.
Developing antivirals or more durable vaccines against IAV has proven difficult because the virus readily alters its genetic material, mutating, rearranging or recombining with other IAV strains within the same cell. This genetic plasticity makes it hard for drug developers to create long‑lasting solutions and continually raises the risk of new pandemic variants.
Part of the problem is the lack of a suitable human in‑vitro system to evaluate new therapies. Animal models of IAV fail to replicate human immune responses, and drug delivery to human lung tissue occurs under different conditions than in animals. Current CRISPR‑based approaches target sequences unique to humans, so their efficacy cannot be tested meaningfully in animals.
A joint effort by the Wyss Institute at Harvard University has overcome these hurdles by combining a microfluidic “breathing” lung alveolus chip, advanced drug‑delivery nanoparticles, and state‑of‑the‑art CRISPR technology. The team engineered CRISPR machinery that recognizes a highly conserved IAV genome sequence, packed it into nanoparticles that specifically bind to lung epithelial cells, and introduced the complex into a microfluidic channel of the lung chip infected with a pandemic IAV strain.
After a single dose, the viral load in the engineered tissue dropped by more than 50 %, and the virus‑induced inflammatory response was markedly reduced. Transcriptomic analysis revealed only minimal off‑target effects. These results demonstrate that the lung chip model offers a more faithful representation of human IAV infection than other pre‑clinical platforms, allowing both efficacy and safety of CRISPR‑RNA therapies to be assessed in a clinically relevant setting.
The study was published in Lab on a Chip. “Our findings show that the human Lung Chip platform is a powerful pre‑clinical tool for testing broad‑spectrum CRISPR‑RNA therapeutics, providing clear evidence of efficacy while revealing only negligible off‑target activity,” said Donald Ingber. “Given the likelihood of future pandemics and the continual seasonal evolution of IAV, pan‑IAV antivirals developed with this platform could help us stay ahead of the virus and save thousands of lives.”
Ingber holds the Judah Folkman Professorship of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professorship of Biologically Inspired Engineering at the School of Engineering and Applied Sciences.
Co‑authors on the paper include Ryan Posey, Haiquing Bai, Amanda Jiang, Pere Dosta, Diana Ocampo‑Alvarado, Robert Plebani, Jie Ji, and Chaitra Belgur.