CRISPR‐Cas13: A Promising Pan‑Flu Antiviral Strategy Under Development

At the October Pandemic Research Alliance Symposium, virologist Wei Zhao presented a novel application of CRISPR‑Cas13 for the prevention and treatment of influenza. While CRISPR‑Cas9 has earned acclaim for correcting genetic diseases, Zhao’s group focuses on Cas13, a CRISPR effector that cleaves RNA rather than DNA. Cas13, a bacterial antiviral enzyme, naturally degrades incoming viral RNA in infected prokaryotic cells. By encoding Cas13 and a virus‑specific guide RNA as messenger RNA (mRNA) and coupling them with lipid‑based nanoparticles, the team can deliver the components directly into human respiratory epithelial cells. The first mRNA drives the endogenous machinery to produce Cas13, while the second guide RNA directs the enzyme to conserved regions within the influenza RNA genome. In a two‑staged protocol, the enzyme cuts the viral RNA, disrupting replication and halting infection at the genetic level. Lead investigator Sharon Lewin notes that because the targeted sequences are conserved across influenza A subtypes, the approach functions as a ‘pan‑flu’ antagonist, unlike conventional antivirals such as oseltamivir that require strain‑specific activity. The envisioned delivery format could be a nasal spray or intramuscular injection, enabling prophylaxis during high‑virulence seasons or rapid post‑exposure therapy. By priming airway cells to express Cas13, the system would act as an engineered first‑line defense, ready to engage the virus upon entry. Preclinical safety studies have been conducted using a lung‑on‑a‑chip platform constructed from human alveolar epithelial and endothelial cells. Researchers exposed the system to multiple influenza strains—including H1N1, H3N2, and 2009‑swine‑flu–derived viruses—demonstrating robust viral suppression and no measurable off‑target RNA cleavage or inflammatory exacerbation. Despite these encouraging results, several hurdles must be addressed before clinical deployment. Nicholas Heaton of Duke University highlights the potential for host immune recognition of the bacterial Cas13 protein and the risk of off‑target editing causing unintended cellular damage. Heaton also cautions that direct antiviral pressure could accelerate viral escape mutations, even within apparently conserved genomic regions. Delivering lipid nanoparticles deep into alveolar spaces remains a technical challenge. Donald Ingber, founding director of Harvard’s Wyss Institute, acknowledges the need for refined aerosolization or targeted inhalation technologies to achieve efficient and uniform distribution of the CRISPR machinery. Parallel efforts are exploring the use of Cas9 to modulate human host factors that influenza exploits for entry, such as the SLC35A1 gene responsible for glycosyltransferase activity that presents viral receptors. By selectively down‑regulating this gene in respiratory tissues, researchers aim to blunt viral attachment while preserving physiological function. While the concept of engineering human cells to produce a viral‑cleaving enzyme is conceptually elegant, the field remains in early developmental stages. Robust in vivo studies in animal models, exhaustive assessment of immunogenicity and genome‑wide specificity, and scalable manufacturing of the delivery platform are requisite next steps. In sum, CRISPR‑Cas13 offers a versatile, sequence‑directed strategy that could transform influenza prophylaxis and therapy. If the technical, immunological, and regulatory challenges can be surmounted, the technology may provide the first adaptive, broad‑spectrum antiviral capable of pre‑empting future influenza pandemics.