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Utilization of Taqman qPCR method for detecting gene doping by adenovirus vector

青木, 海 筑波大学 DOI:10.15068/0002001893

2021.11.17

概要

Doping is an act of raising competitive abilities to achieve success by using substances or methods prohibited in sports [Japan Anti-Doping Agency (JADA). What Is Anti-Doping?]. Doping in sports, especially in festivals such as the Olympic Games and in world or local championships for various competitions, is considered illegal and against the spirit of the game. The World Anti-Doping Agency (WADA) was established in 1999, and has been involved in scientific research on doping, anti-doping education, development of anti-doping strategies, and monitoring of the World Anti-Doping Code (hereafter the Code) [The World Anti-Doping Agency (WADA)] to ensure soundness and fairness in sports worldwide.

　With the rapid progress of genetic engineering technology and gene therapy, WADA has been strongly alerted against gene doping. Since its early days, WADA has added “gene doping” to its prohibited list. The difference between gene therapy and gene doping for an example is shown in Figure 1. Subsequently, in 2004, WADA created a panel of experts on gene doping to investigate the latest advances in the field of gene therapy, and the methods for detecting doping [WADA. Anti-Doping Textbook]. In January 2018, WADA extended the ban on gene doping to include all forms of gene editing. Therefore, the list of prohibited substances currently includes “gene editing agents designed to alter genome sequences and/or the transcriptional or epigenetic regulation of gene expression” [WADA. World Anti-Doping Code with International Standard, Prohibited List]. However, there are no established standard methods for detecting or preventing gene doping to date. The difference between doping and gene doping, which may be particularly problematic, is shown in Figure 2.

　In recent years, genetic engineering technology has rapidly advanced, resulting in the progression of gene therapy. In gene therapy, various viral vectors have been frequently devised and applied. Vectors based on recombinant adeno-associated viruses (rAAV) and recombinant adenoviruses (rAdV) have been widely used in clinical trials and animal experiments for investigating gene therapy. For example, rAAV vectors have been applied in the treatment of diseases, such as Duchenne muscular dystrophy (DMD) [Duan et al. 2018], hemophilia B [High et al. 2016; Naso et al. 2017], and Leber congenital amaurosis (LCA) [Kumaran et al. 2017; Sharif et al. 2017], during clinical trials or animal experiments as a form of gene therapy. Moreover, rAdV vectors also have been applied in gene therapy for the treatment of certain human cancers [Wold et al. 2014; Lee et al. 2017; Xia et al. 2018]. In China, two rAdV vector-based gene therapy products, namely Gendicine (Shenzhen SiBiono GeneTech Co., Ltd., Shenzhen, China) [Xia et al. 2018; Zhang et al. 2018] and Oncorine (Sunway Biotech Co., Ltd., Taipei, Taiwan), were approved for clinical use in humans to treat head and neck cancer, and were released into the commercial market in 2003 and 2006, respectively [Liang et al. 2018]. Additionally, rAdV vectors were the most commonly used vectors in approved clinical trials of gene therapy (541 cases, 18% of the total) worldwide until December 2018 [The Journal of Gene Medicine. Charts and Tables, Vectors.] (Table 1). It can be assumed that gene doping methods may employ clinical trial methods. Therefore, there is a possibility that rAAV or rAdV vectors, especially rAdV vectors, can be used as gene doping agents to enhance athletic performance by artificially modifying gene expression in specific human organs. In this study, I focused on rAdV vectors, since rAdV vectors are the most commonly used in clinical trials (Table 1), and are also used as prescription drugs. Therefore, the aim of this doctoral dissertation was to establishe the detection methods for gene doping using rAdV vectors.

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神保貴宏, 村田直哉, 田村遵一, 沢村守夫, 楢原伸裕, 村上博和, 久保田一雄, 土屋純, 成清卓二. 顆粒球コロニー刺激因子(Granulocyte colony-stimulating factor)およびエリスロポエチン(Erythropoietin)の投与により著明な白血球増加を認めた老年者骨髄異形成症候群の1例. 老年医学会雑誌,1993,30巻, 3号, 212-215

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