Gene transfer to hemophilia A mice via oral delivery of FVIII-chitosan nanoparticles
Gene transfer to hemophilia A mice via oral delivery of FVIII-chitosan nanoparticles
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DOI：
10.1016/j.jconrel.2008.06.019
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发表时间：
2008-12-18
影响因子：
10.8
通讯作者：
Leong, Kam W.
中科院分区：
文献类型：
--
作者：
Bowman, Katherine;Sarkar, Rita;Leong, Kam W.
有效口服非病毒基因载体将代表一种新颖且有吸引力的治疗性基因转移策略。为了评估这种方法的潜力，我们研究了由壳聚糖和因子 VIII DNA 组成的 DNA 复合物的口服基因递送功效。给A型血友病小鼠口服壳聚糖纳米粒子后，在局部和全身组织中均检测到转基因DNA。通过显色和凝血酶生成测定在血浆中检测到功能性因子 VIII 蛋白，在分娩后第 22 天达到 2-4% FVIII 的峰值水平。此外，在给予 DNA 一个月后的出血挑战中，给予 250-600 μg 壳聚糖纳米颗粒中的 FVIII DNA 的小鼠中，有 13/20 的小鼠出现表型校正，而给予裸 FVIII DNA 的小鼠为 1/13，未治疗的小鼠为 0/6。虽然需要进一步优化才能使这种类型的递送系统适用于血友病 A 基因治疗，但研究结果表明口服、非病毒递送用于基因医学应用的可行性。 (C) 2008 Elsevier B.V. 保留所有权利。
Effective oral delivery of a non-viral gene carrier would represent a novel and attractive strategy for therapeutic gene transfer. To evaluate the potential of this approach, we studied the oral gene delivery efficacy of DNA polyplexes composed of chitosan and Factor VIII DNA. Transgene DNA was detected in both local and systemic tissues following oral administration of the chitosan nanoparticles to hemophilia A mice. Functional factor VIII protein was detected in plasma by chromogenic and thrombin generation assays, reaching a peak level of 2-4% FVIII at day 22 after delivery. In addition, a bleeding challenge one month after DNA administration resulted in phenotypic correction in 13/20 mice given 250-600 mu g of FVIII DNA in chitosan nanoparticles, compared to 1/13 mice given naked FVIII DNA and 0/6 untreated mice. While further optimization would be required to render this type of delivery system practical for hemophilia A gene therapy, the findings suggest the feasibility of oral, non-viral delivery for gene medicine applications. (C) 2008 Elsevier B.V. All rights reserved.