title: Preclinical safety evaluation of recombinant adeno-associated virus 2 vector encoding human tumor necrosis factor receptor-immunoglobulin Fc fusion gene.
abstract: Recombinant adeno-associated virus (rAAV) 2 vector gene therapy offers promise for the healing of Rheumatoid arthritis. To support the clinical development of the candidate gene therapeutic product in China, a comprehensive preclinical safety assessment of rAAV2 encoding human TNF receptor-immunoglobulin Fc fusion gene (rAAV2/human TNFR:Fc), were conducted in 3 species of experimental animals. No abnormal findings were observed in mice following single intravenous administration with test article. Compared with the control group, no differences in mean body weight, food consumption in rats and monkeys following the repeated intraarticular administration with rAAV2/human TNFR:Fc. There were also no significant adverse effects due to treatment noted by clinical chemistry, hematology and pathology assessments. After intraarticular administration with rAAV2/human TNFR:Fc, the vector DNA initially distributed to spleen, lymph nodes, and joint synovium. The vector DNA cleared rapidly as it could be detected mainly at the site of injection by 91 d post-administration (182 d for monkey). Taken together, localized delivery of rAAV2/human TNFR:Fc showed no significant toxicity in mice, rats, and monkeys, which support the planned clinical evaluation of this product.
authors.affiliation: a National Center for Safety Evaluation of Drugs, National Institutes of Food and Drug Control , Beijing , China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zhou
authors.affiliation: a National Center for Safety Evaluation of Drugs, National Institutes of Food and Drug Control , Beijing , China.
authors.forename: Lianzhong
authors.initials: L
authors.lastname: Shen
authors.affiliation: a National Center for Safety Evaluation of Drugs, National Institutes of Food and Drug Control , Beijing , China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: a National Center for Safety Evaluation of Drugs, National Institutes of Food and Drug Control , Beijing , China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: a National Center for Safety Evaluation of Drugs, National Institutes of Food and Drug Control , Beijing , China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Qi
authors.affiliation: b AGTC Gene Technology Company Ltd. , Beijing , China.
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhao
authors.affiliation: b AGTC Gene Technology Company Ltd. , Beijing , China.|c Beijing Fiveplus Molecular Medicine Institute , Beijing , China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wu
authors.affiliation: a National Center for Safety Evaluation of Drugs, National Institutes of Food and Drug Control , Beijing , China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects*; D007141:Immunoglobulin Fc Fragments / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D007155:Immunologic Factors / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; D011993:Recombinant Fusion Proteins
keywords: gene therapy; intraarticular; preclinical safety evaluation; rAAV2/human TNFR:Fc; rheumatoid arthritis
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