Non-invasive administration of AAV to target lung parenchymal cells and develop SARS-CoV-2-susceptible mice

Yang, Myeon‐Sik; Park, Min-Jung; Lee, Junhyeong; Oh, Byungkwan; Kang, Kyung‐Won; Kim, Yeon-Hwa; Lee, Sang-Myeong; Lim, Je‐Oh; Jung, Tae-Yang; Park, Jong‐Hwan; Park, Seok‐Chan; Lim, Yunsook; Hwang, Soon B.; Lyoo, Kwang‐Soo; Kim, Dong-il; Kim, Bumseok

doi:10.1016/j.ymthe.2022.01.010

Cited by 15 publications

(3 citation statements)

References 44 publications

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“…These results are consistent with previous observations of improved lung delivery for AAV6 compared with AAV8 and broader tropism of the AAV9 capsid variant relative to AAV6 or AAV8. 37 , 38 Immunofluorescent staining (IF) of lung tissue from animals intubated with either AAV6-CAG-GFP or AAV9-CAG-GFP showed high %GFP expression in AECII compared with modest expression with AAV8-CAG-GFP ( Figures S1 E and S1F). Relative to AAV9, AAV6 provided greater transduction efficiency in club cells ( Figures S1 E and S1F).…”

Section: Resultsmentioning

confidence: 99%

Population-wide gene disruption in the murine lung epithelium via AAV-mediated delivery of CRISPR-Cas9 components

Chen¹,

Durinck²,

Patel³

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Section: Resultsmentioning

confidence: 99%

Population-wide gene disruption in the murine lung epithelium via AAV-mediated delivery of CRISPR-Cas9 components

Chen¹,

Durinck²,

Patel³

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…This short time course compares favorably with the much longer time required to develop transgenic mice expressing hACE2. Further, hACE2 expression after AAV-hACE2 intranasal inoculation is restricted to the respiratory system whereas transgene expression may be widespread [ 26 , 50 , 51 ] and result in infection in organs that are not usually associated with SARS-CoV-2 infection such as direct infection in brains of K18 hACE2 transgenic mice, which is a major factor contributing to the fatal outcome. Although AAV6.2FF-Luc transduced mice also had lesions and inflammation upon SARS-CoV-2 infection in the absence of SARS-CoV-2 antigen detection, inflammation associated with DMEM intranasal instillation of liquid into the lungs has been shown to cause instillation-associated histopathology [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterization of a SARS-CoV-2-Susceptible Mouse Model Using Adeno-Associated Virus (AAV6.2FF)-Mediated Respiratory Delivery of the Human ACE2 Gene

Tailor

Warner

Griffin

et al. 2022

Viruses

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) that has caused a pandemic with millions of human infections. There continues to be a pressing need to develop potential therapies and vaccines to inhibit SARS-CoV-2 infection to mitigate the ongoing pandemic. Epidemiological data from the current pandemic indicates that there may be sex-dependent differences in disease outcomes. To investigate these differences, we proposed to use common small animal species that are frequently used to model disease with viruses. However, common laboratory strains of mice are not readily infected by SARS-CoV-2 because of differences in the angiotensin-converting enzyme 2 (ACE2), the cellular receptor for the virus. To overcome this limitation, we transduced common laboratory accessible strains of mice of different sexes and age groups with a novel a triple AAV6 mutant, termed AAV6.2FF, encoding either human ACE2 or luciferase via intranasal administration to promote expression in the lung and nasal turbinates. Infection of AAV-hACE2-transduced mice with SARS-CoV-2 resulted in high viral titers in the lungs and nasal turbinates, establishment of an IgM and IgG antibody response, and modulation of lung and nasal turbinate cytokine profiles. There were insignificant differences in infection characteristics between age groups and sex-related differences; however, there were significant strain-related differences between BALB/c vs. C57BL/6 mice. We show that AAV-hACE2-transduced mice are a useful for determining immune responses and for potential evaluation of SARS-CoV-2 vaccines and antiviral therapies, and this study serves as a model for the utility of this approach to rapidly develop small-animal models for emerging viruses.

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“…Pediatric patients with COVID-19, who have better outcomes than adults, were also found to have higher levels of some innate molecules and increased innate immune responses compared to older patients [ 24 ]. Mice lacking the IFNAR receptor have increased susceptibility to SARS-CoV-2 [ 25 ]. Supplemental IFN-I has been tested as a treatment for SARS-CoV-1, MERS-CoV, and SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

The Evolutionary Dance between Innate Host Antiviral Pathways and SARS-CoV-2

Aliyari

Quanquin

Pernet³

et al. 2022

Pathogens

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Compared to what we knew at the start of the SARS-CoV-2 global pandemic, our understanding of the interplay between the interferon signaling pathway and SARS-CoV-2 infection has dramatically increased. Innate antiviral strategies range from the direct inhibition of viral components to reprograming the host’s own metabolic pathways to block viral infection. SARS-CoV-2 has also evolved to exploit diverse tactics to overcome immune barriers and successfully infect host cells. Herein, we review the current knowledge of the innate immune signaling pathways triggered by SARS-CoV-2 with a focus on the type I interferon response, as well as the mechanisms by which SARS-CoV-2 impairs those defenses.

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Non-invasive administration of AAV to target lung parenchymal cells and develop SARS-CoV-2-susceptible mice

Cited by 15 publications

References 44 publications

Population-wide gene disruption in the murine lung epithelium via AAV-mediated delivery of CRISPR-Cas9 components

Population-wide gene disruption in the murine lung epithelium via AAV-mediated delivery of CRISPR-Cas9 components

Generation and Characterization of a SARS-CoV-2-Susceptible Mouse Model Using Adeno-Associated Virus (AAV6.2FF)-Mediated Respiratory Delivery of the Human ACE2 Gene

The Evolutionary Dance between Innate Host Antiviral Pathways and SARS-CoV-2

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