Intranasal gene therapy to prevent infection by SARS-CoV-2 variants

• Published in: PLoS pathogens 2021-07, Vol.17 (7), p.e1009544
• Main Authors: Sims, Joshua J, Greig, Jenny A, Michalson, Kristofer T, Lian, Sharon, Martino, R Alexander, Meggersee, Rosemary, Turner, Kevin B, Nambiar, Kalyani, Dyer, Cecilia, Hinderer, Christian, Horiuchi, Makoto, Yan, Hanying, Huang, Xin, Chen, Shu-Jen, Wilson, James M
• Format: Article
• Language: English
• Subjects: ACE2; Administration, Intranasal; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - biosynthesis; Angiotensin-Converting Enzyme 2 - genetics; Animals; Binding sites; Biology and life sciences; Complications; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - metabolism; COVID-19 Drug Treatment; COVID-19 vaccines; Dependovirus; Disease transmission; Enzymes; Gene therapy; Genetic Therapy; Genetic Vectors; Humans; Infections; Intranasal administration; Libraries; Medicine and health sciences; Methods; Mice; Mice, Transgenic; Monoclonal antibodies; Mutation; Pandemics; Pathogenicity; Pathogens; Peptidyl-dipeptidase A; Protein folding; Proteins; Research and Analysis Methods; SARS-CoV-2 - genetics; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Vaccination; Vaccines; Viral diseases; Viruses; Yeast
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009544

SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. Here we present an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by one of the many pre-emergent, ACE2-dependent CoVs that are poised for zoonosis.