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.

Keywords:

• gene therapy
• intraarticular
• preclinical safety evaluation
• rAAV2/human TNFR:Fc
• rheumatoid arthritis

Disclosure of potential conflicts of interest

Aizhi Zhao and Xiaobing Wu were employees of AGTC Gene Technology Company Ltd as the work was done. The other authors declare no conflicts of interest.

Acknowledgments

We would like to thank Ming Li, Li Sun, Xin Li, Yufa Miao, Fang Liu, Yanwei Yang, and Di Zhang for excellent technical assistant in animal and pathological studies. We also thank Dr Hairuo Wen for reviewing and revising this manuscript.

Funding

This work was partly supported by National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 2012ZX09302001).