Human Organ Chip technology sets stage for pan-influenza A CRISPR RNA therapies
Human lung alveolus chip infection model enables investigation of viral replication, inflammatory responses, and genetic off-target effects of a novel pan-influenza CRISPR therapy
By Benjamin Boettner
Boston – The Influenza A virus (IAV) has been the cause of six major flu pandemics, responsible for 50 to 100 million deaths globally. In the U.S. alone, it is estimated that, despite seasonally updated vaccines, IAV infections still lead to 140,000 to 710,000 hospitalizations and 12,000 to 52,000 deaths annually.
The development of antiviral treatments against IAV – or more durable vaccination approaches for that matter – has been extremely challenging because IAV readily develops resistance against them by changing its genetic makeup. To date, its ability to “mutate,” rearrange its genetic information or even recombine it with that of other IAV viruses infecting the same cell has been an unsurmountable challenge for drug developers, and presents a constant risk for new pandemic strains to emerge.
The search for an effective weapon against IAV’s ever-changing genetic makeup has been hampered by the absence of a suitable human in vitro model for testing new treatments. This challenge is compounded by the fact that animal models of IAV infection fail to accurately replicate human immune responses, and drug delivery to human lung tissue operates under different conditions than in animals. New approaches based on CRISPR gene editing technology are being explored, but the sequences being targeted are so human-specific that studies can’t be carried out in animal models in a meaningful way.
Now, a new collaborative study from the Wyss Institute for Biologically Inspired Engineering at Harvard University addressed these challenges by simultaneously leveraging a microfluidic “breathing” human lung alveolus chip (Lung Chip) model of IAV infection developed in the group of Founding Director Donald Ingber, M.D., Ph.D., drug delivery platforms advanced by Associate Director Natalie Artzi, Ph.D. and her group, as well as state-of-the-art CRISPR technology. The team achieved this by designing CRISPR machinery targeting a strongly conserved sequence in IAV’s genome, packaging it up in tiny nanoparticles with affinity to lung epithelial cells, and delivering the loaded particles to lung epithelial cells lining a microfluidic channel in the Lung Chip that were infected with a pandemic IAV. As a result, the load of the virus in the engineered tissue was reduced by more than 50% after a single administration of the treatment, and the host inflammatory response caused by the virus was significantly blunted. Importantly, only minimal off-target effects, as revealed by transcriptomic analysis, occurred in the system. Thus, this Organ Chip model that better mimics human IAV infection than other preclinical models enables the efficacy and safety of CRISPR RNA therapies to be evaluated in a more clinically relevant way than earlier approaches. The findings are published in Lab on a Chip.
“Our findings demonstrate that the human Lung Chip model of IAV infection is a highly valuable preclinical testbed for CRISPR RNA therapeutics that act broadly across virus strains because it not only reports on their efficacy in a human-relevant manner but, importantly, also allows assessment of their potential off-target effects, which we find so far are minimal,” said Ingber. “Given the high likelihood of future pandemics and natural seasonal variation of IAV, such pan-IAV antiviral treatments could help us get ahead of the virus and, potentially, save thousands of lives.” Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.
Other authors on the study included Ryan Posey, Haiquing Bai, Amanda Jiang, Pere Dosta, Diana Ocampo-Alvarado, Robert Plebani, Jie Ji, and Chaitra Belgur. The study was supported by Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement HR0011-22-2-0017, and the Wyss Institute at Harvard University.
PRESS CONTACT
Wyss Institute for Biologically Inspired Engineering at Harvard University
Benjamin Boettner, benjamin.boettner@wyss.harvard.edu
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The Wyss Institute for Biologically Inspired Engineering at Harvard University (www.wyss.harvard.edu) is a research and development engine for disruptive innovation powered by biologically-inspired engineering with visionary people at its heart. Our mission is to transform healthcare and the environment by developing ground-breaking technologies that emulate the way Nature builds and accelerate their translation into commercial products through formation of startups and corporate partnerships to bring about positive near-term impact in the world. We accomplish this by breaking down the traditional silos of academia and barriers with industry, enabling our world-leading faculty to collaborate creatively across our focus areas of diagnostics, therapeutics, medtech, and sustainability. Our consortium partners encompass the leading academic institutions and hospitals in the Boston area and throughout the world, including Harvard’s Schools of Medicine, Engineering, Arts & Sciences and Design, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité – Universitätsmedizin Berlin, University of Zürich, and Massachusetts Institute of Technology.
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