Beer S J, Matthews C B, Stein C S, Ross B D, Hilfinger J M, Davidson B L
Department of Neurosurgery, University of Iowa, Iowa City, USA.
Gene Ther. 1998 Jun;5(6):740-6. doi: 10.1038/sj.gt.3300647.
Adenovirus-mediated gene transfer has application to the treatment of diseases of the central nervous system. We demonstrate that a limitation to its use in vivo is an inability to redose to the brain. We show that one factor inhibiting re-dosing is the development of neutralizing anti-adenoviral antibodies. Encapsulation of recombinant adenovirus vectors in poly(lactic/glycolic acid) (PLGA) copolymer enables infection in vitro, in the presence of neutralizing antibodies and results in the release of viable virus for over 100 h. Importantly, encapsulated adenovirus also shows diminished immunogenicity in vivo. Mice immunized with encapsulated recombinant adenoviral vectors show a greater than 45-fold reduction in anti-adenovirus titers relative to non-encapsulated vectors. An extended release formulation of adenovirus that reduces viral immunogenicity and sequesters the viral particle form antibody exposure may improve in vivo efficacy.
腺病毒介导的基因转移已应用于中枢神经系统疾病的治疗。我们证明，其在体内使用的一个限制是无法再次给药至脑部。我们表明，抑制再次给药的一个因素是中和抗腺病毒抗体的产生。将重组腺病毒载体封装在聚乳酸/乙醇酸（PLGA）共聚物中可在体外存在中和抗体的情况下实现感染，并导致活病毒释放超过100小时。重要的是，封装的腺病毒在体内也显示出免疫原性降低。与未封装的载体相比，用封装的重组腺病毒载体免疫的小鼠抗腺病毒滴度降低了45倍以上。一种可降低病毒免疫原性并使病毒颗粒免受抗体暴露的腺病毒缓释制剂可能会提高体内疗效。
