Shi Xiaoxia, Ykema Matthew Ryan, Hazenoot Jaco, Ten Bloemendaal Lysbeth, Mancini Irene, Odijk Machteld, de Haan Peter, Bosma Piter J
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands.
Amarna Therapeutics B.V., Leiden, the Netherlands.
Mol Ther Methods Clin Dev. 2018 Feb 27;9:225-233. doi: 10.1016/j.omtm.2018.02.010. eCollection 2018 Jun 15.
Gene therapy has been shown to be a feasible approach to treat inherited disorders . Among the currently used viral vector systems, adeno-associated virus (AAV) vectors are the most advanced and have been applied in patients successfully. An important drawback of non-integrating AAV vectors is their loss of expression upon cell division, while repeating systemic administration lacks efficacy due to the induction of neutralizing antibodies. In addition, a significant percentage of the general population is not eligible for AAV-mediated gene therapy due to pre-existing immunity. Development of additional viral vectors may overcome this hurdle. Simian virus 40 (SV40)-derived vectors have been reported to transduce different tissues, including the liver, and prevalence of neutralizing antibodies in the general population is very low. This renders recombinant SV40 (rSV40) vector an interesting candidate for effective (re-)administration. Clinical use of SV40 vectors is in part hampered by less advanced production methods compared to AAVs. To optimize the production of rSV40 and make it better suitable for clinical practice, we developed a production system that relies on Cre recombinase-mediated removal of the bacterial plasmid backbone.
基因治疗已被证明是治疗遗传性疾病的一种可行方法。在目前使用的病毒载体系统中，腺相关病毒（AAV）载体最为先进，并已成功应用于患者。非整合型AAV载体的一个重要缺点是其在细胞分裂时会丧失表达，而重复进行全身给药由于会诱导中和抗体而缺乏疗效。此外，由于预先存在的免疫力，相当一部分普通人群不适合接受AAV介导的基因治疗。开发其他病毒载体可能会克服这一障碍。据报道，猿猴病毒40（SV40）衍生载体可转导包括肝脏在内的不同组织，并且普通人群中中和抗体的流行率非常低。这使得重组SV40（rSV40）载体成为有效（再）给药的一个有吸引力的候选者。与AAV相比，SV40载体的临床应用部分受到生产方法不够先进的阻碍。为了优化rSV40的生产并使其更适合临床实践，我们开发了一种依赖于Cre重组酶介导去除细菌质粒骨架的生产系统。
