Browsing by Author "Zhou, Zhichang"

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    Intranasal HD-Ad vaccine protects the upper and lower respiratory tracts of hACE2 mice against SARS-CoV-2
    (2021-12-08) Cao, Huibi; Mai, Juntao; Zhou, Zhichang; Li, Zhijie; Duan, Rongqi; Watt, Jacqueline; Chen, Ziyan; Bandara, Ranmal A.; Li, Ming; Ahn, Sang K.; Poon, Betty; Christie-Holmes, Natasha; Gray-Owen, Scott D.; Banerjee, Arinjay; Mossman, Karen; Kozak, Rob; Mubareka, Samira; Rini, James M.; Hu, Jim; Liu, Jun
    Abstract Background The ongoing COVID-19 pandemic has resulted in 185 million recorded cases and over 4 million deaths worldwide. Several COVID-19 vaccines have been approved for emergency use in humans and are being used in many countries. However, all the approved vaccines are administered by intramuscular injection and this may not prevent upper airway infection or viral transmission. Results Here, we describe a novel, intranasally delivered COVID-19 vaccine based on a helper-dependent adenoviral (HD-Ad) vector. The vaccine (HD-Ad_RBD) produces a soluble secreted form of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and we show it induced robust mucosal and systemic immunity. Moreover, intranasal immunization of K18-hACE2 mice with HD-Ad_RBD using a prime-boost regimen, resulted in complete protection of the upper respiratory tract against SARS-CoV-2 infection. Conclusion Our approaches provide a powerful platform for constructing highly effective vaccines targeting SARS-CoV-2 and its emerging variants.
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    Site-specific Human CFTR Gene Integration through CRISPR/Cas9-mediated Targeting
    (2020-11) Zhou, Zhichang; Hu, Jim; Laboratory Medicine and Pathobiology
    Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). It leads to multiple organ dysfunctions, where lung disease is the major cause of morbidity and mortality. Gene therapy for CF lung disease is still challenged with achieving sustained and sufficient therapeutic transgene expression. The advancement of site-specific endonuclease, CRISPR/Cas9, sheds light on permanent CFTR gene correction. We proposed a novel strategy that can precisely integrate therapeutic human CFTR (hCFTR) gene into genomic safe harbor through Cas9-induced homology directed repair (HDR), via an all-in-one helper-dependent adenoviral (HD-Ad) vector delivery. This strategy can target CFTR mutations regardless of mutation types. We have demonstrated a 10% integration efficiency in porcine CFTR-/- cells. The integrated hCFTR gene is sustainably and functionally expressed in cells. By co-delivering another HD-Ad vector to express HDR factor, Exo1 or CtIP, transgene integration efficiency is further enhanced by an average of 2-fold. We have also proven that the airway basal stem cells can be targeted by our hCFTR gene editing system in vitro. Moreover, functional hCFTR is expressed in primary CFTR-/- porcine airway epithelial cells. Overall, this study demonstrates that our HD-Ad vector-based hCFTR gene targeting system has the potential to be adapted for treating CF lung disease.