Reducing off target viral delivery in ovarian cancer gene therapy using a protease-activated AAV2 vector platform

JOURNAL OF CONTROLLED RELEASE

卷:307

Article

Tong, J. G.¹  Evans, A. C.¹  Ho, M. L.¹  Guenther, C. M.¹  Brun, M. J.²  Judd, J.¹  Wu, E.¹  Suh, J.^1,2,3 

[1] Rice Univ, Dept Bioengn, 6100 Main St, Houston, TX 77005 USA

[2] Rice Univ, Dept Chem & Biomol Engn, 6100 Main St, Houston, TX 77005 USA

[3] Rice Univ, Syst Synthet & Phys Biol Program, 6100 Main St, Houston, TX 77005 USA

关键词: Adeno-associated virus;    AAV;    Gene therapy;    Gene delivery;    Viral vector;    Stimulus-responsive;    Activatable;    de-targeting;    Capsid engineering;    Cancer gene therapy;    Ovarian cancer;    Protease;    Matrix metalloproteinase;    Provector;   

DOI  :  10.1016/j.jconrel.2019.06.034

来源: Elsevier

【 摘 要 】

Gene therapy is a promising strategy for treating metastatic epithelial ovarian cancer (EOC). However, efficient vector targeting to tumors is difficult and off-target effects can be severely detrimental. Most vector targeting approaches rely on surface receptors overexpressed on some subpopulation of cancer cells. Unfortunately, there is no universally expressed cell surface biomarker for tumor cells. As an alternative, we developed an adeno-associated virus (AAV) based Provector whose cellular transduction can be activated by extracellular proteases, such as matrix metalloproteinases (MMP) that are overexpressed in the tumor microenvironments of the most aggressive forms of EOC. In a non-tumor bearing mouse model, the Provector demonstrates efficient detargeting of healthy tissues, especially the liver, where viral delivery is < 1% of AAV2. In an orthotopic HeyA8 tumor model of EOC, the Provector maintains decreased off-target delivery in the liver and other tissues but with no loss in tumor delivery. Notably, approximately 10% of the injected Provector is still detected in the blood at 24 h while > 99% of injected AAV2 has been cleared from the blood by 1 h. Furthermore, mouse serum raised against the Provector is 16-fold less able to neutralize Provector transduction compared to AAV2 serum neutralizing AAV2 transduction (1:200 vs 1:3200 serum dilution, respectively). Thus, the Provector appears to generate less neutralizing antibodies than AAV2. Importantly, serum against AAV2 does not neutralize the Provector as well as AAV2, suggesting that pre-existing antibodies against AAV2 would not negate the clinical application of Provectors. Taken together, we present an EOC gene delivery vector platform based on AAV with decreased off-target delivery without loss of on-target specificity, and greater immunological stealth over the traditional AAV2 gene delivery vector.

【 授权许可】

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