摘要
有效传递仍旧是基于基因治疗发展中的主要阻碍。虽然已经产生了从总体上改善传递的技术进展,但是为达到治疗作用仍旧需要可控传递。基因电转(GET)可以用来完成此项内容。可以谨慎选择传递参数如:振幅、脉冲的持续时间和数目及质粒创建,以便使局部表达达到适度水平。我们前期实验表明采用电转移把细胞因子白介素12(IL-12)直接转导如肿瘤细胞,可以在临床前和临床研究中产生局部和系统性抗肿瘤作用。采用这种模型我们假设,利用GET调节的局部基因表达能够影响治疗结果。为了对此进行测试,我们采用多种GER方案和质粒来实现IL-12局部不同水平表达。我们发现局部的基因高表达并没有导致更好的治疗结果。这也提示基因表达水平和可能的持续时间在调节宿主免疫应答抵抗黑素瘤中是至关重要的。这些数据也强调了在选择GET参数时考虑理想的免疫治疗结果的重要性。
关键词: 细胞因子,电转,基因治疗,免疫疗法,白介素-12,黑素瘤
Current Gene Therapy
Title:Controlled Gene Delivery Can Enhance Therapeutic Outcome for Cancer Immune Therapy for Melanoma
Volume: 15 Issue: 1
Author(s): Shawna A. Shirley, Cathryn G. Lundberg, Fanying Li, Niculina Burcus and Richard Heller
Affiliation:
关键词: 细胞因子,电转,基因治疗,免疫疗法,白介素-12,黑素瘤
摘要: Effective delivery still remains a major hurdle in the development of gene based therapies. While technological advances have occurred that have improved delivery in general, there is still a need for controlled delivery in order to achieve therapeutic effects. Gene electrotransfer (GET) can be utilized to accomplish this. Careful selection of parameters used for delivery such as amplitude, duration and number of pulses as well as plasmid construct can be manipulated in order to achieve appropriate levels of local expression. Previously we have shown that direct delivery of the therapeutic cytokine, interleukin 12 (IL-12), to tumors using electrotransfer can generate local and systemic anti-tumor effects in pre-clinical and clinical studies. Using this model we hypothesized that modulating local gene expression using GET can affect therapeutic outcome. To test this, we used multiple GET protocols and plasmids to achieve varying levels of local IL-12 expression. We found that high local gene expression did not give rise to a better therapeutic outcome. This suggests the level and possibly the duration of gene expression are important in mediating the host immune response against melanoma. These data also emphasize the importance of considering the desired immune outcome of the therapy when selecting parameters for GET.
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Shawna A. Shirley, Cathryn G. Lundberg, Fanying Li, Niculina Burcus and Richard Heller , Controlled Gene Delivery Can Enhance Therapeutic Outcome for Cancer Immune Therapy for Melanoma, Current Gene Therapy 2015; 15 (1) . https://dx.doi.org/10.2174/1566523214666141121111630
DOI https://dx.doi.org/10.2174/1566523214666141121111630 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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