Ziying Yan, PhD

Portrait
Research Associate Professor
Member, Center for Gene Therapy
Associate Research Scientist
Associate Member, Center for Gene Therapy
Assistant Research Scientist
Post-doctoral Fellow
Associate Professor
Assistant Professor
Research Associate Professor of Anatomy and Cell Biology

Contact Information

Office: 1-111B-1 BSB
51 Newton Road
Iowa City, IA 52242
319-335-9855

Education

BS, Biochemistry, Sun Yat-Sen University
MS, Molecular Biology, Sun Yat-Sen University
PhD, Virology, Chinese Academy of Preventive Medicine (State Key Lab for Molecular, Virology, and Genetic Engineering

Post Doctoral Fellow, Anatomy and Cell Biology, University of Iowa

Research Summary

Our goal is to develop an efficient viral vector for the application in the human pulmonary disease gene therapy, with emphasis on cystic fibrosis (CF). CF a lethal autosomal-recessive disorder that affects over 30,000 in the US alone, the chronic lung infection is the major cause of morbidity and mortality in CF. The basis of CF is a defect in a single gene (cystic fibrosis transmembrane conductance regulator, CFTR), gene therapy of CF lung disease is the best hope for correcting this condition. However, the human lung has evolved highly effective barriers to resist foreign gene transfer. Recombinant adeno-associated virus vector (rAAV) has been successfully used to treat a number of inherited and acquired human diseases, but failed in clinical trials for CF gene therapy to the lung, mostly due to its low tropism for the airway and its small packaging capacity, which precludes incorporation of full-length CFTR with effective promoter. A vector of derived from a virus naturally infecting human airway is expected to bypass both the extra- and intracellular barriers preventing the rAAV-mediated CFTR gene addition to CF airway epithelium. Human bocavirus 1 (HBoV1), a relative of AAV in the parvovirus family, is a human respiratory virus, whose natural host tissue is human airway. Our research pertains to the molecular virology of human bocavirus (HBoV1), as well as to the development bocavirus-based vectors. We found that HBoV1 can establish a productive infection in human airway epithelial cultures at an air-liquid interface (HAE-ALI) at a very high efficiency. To utilize the HBoV1’s properties of native tropism for human airway and large genome size (5.5kb) for a safer transduction vector for CF gene therapy, whereas to eliminate the safety concerns of HBoV1 as a human pathogen, we engineered a novel parvovirus cross-genus hybrid vector, rAAV2/HBoV1, by pseudopackaging the clinical-proven safe rAAV2 genome into HBoV1 capsid. The rAAV2/HBoV1 vector can be produced in HEK293 cells efficiently; it demonstrates remarkable efficiency in transducing the apical membrane of human airway epithelia and 18% larger packaging capacity than rAAV, overcoming the major weaknesses contributed to the failure of rAAV in CF clinical trials. Our studies have shown that a rAAV2/HBoV1 vector, which harbors a 5.2kb cassette encoding the CMV-ß-actin promoter driving the full-length CFTR cDNA (coding sequence), partially corrects the CFTR-specific Cl- channel defect in polarized CF HAE-ALI. Our studies also have demonstrated that rAAV2/HBoV1 efficiently transduces ferret lungs. Current research is focused on understanding the transduction biology of rAAV2/HBoV1 in various human airway models and ferret lung airway in vivo. Preclinical data necessary for applying rAAV2/HBoV1 in CF gene therapy will be studied using the CF ferret models.