A Nanostructured Lipid Carrier for Delivery of a Replicating Viral RNA Provides Single, Low-Dose Protection against Zika
A Nanostructured Lipid Carrier for Delivery of a Replicating Viral RNA Provides Single, Low-Dose Protection against Zika
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DOI：
10.1016/j.ymthe.2018.07.010
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发表时间：
2018-10-03
影响因子：
12.4
通讯作者：
Van Hoeven, Neal
中科院分区：
文献类型：
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作者：
Erasmus, Jesse H.;Khandhar, Amit P.;Van Hoeven, Neal
自从近20年前首次证明注射RNA分子的体内基因表达以来，1基于RNA的治疗领域正在取得重大进展，许多癌症和传染病靶点进入临床试验。2.这一成功的关键是在知识和应用输送制剂方面取得的进展。目前，各种脂质纳米颗粒（LNP）平台处于最前沿，但支撑LNP制剂的封装方法抵消了RNA疫苗的合成和快速反应性质。4第二，利比里亚国家警察配制的RNA稳定性有限，无法为大流行病做好准备而储存。5在这里，我们展示了一种双小瓶方法的发展，其中递送制剂，一种高度稳定的纳米结构脂质载体（NLC），可以与靶RNA分开制造和储存，靶RNA在给药前混合。此外，对NLC的特定物理化学修饰调节免疫应答，增强或减弱中和抗体应答。我们将这种方法与编码寨卡病毒（ZIKV）抗原的复制型病毒RNA（rvRNA）相结合，并证明了低至10 ng的单次剂量可以完全保护小鼠免受致命的ZIKV攻击，这可能是迄今为止任何寨卡疫苗中最有效的方法。
Since the first demonstration of in vivo gene expression from an injected RNA molecule almost two decades ago, 1 the field of RNA-based therapeutics is now taking significant strides, with many cancer and infectious disease targets entering clinical trials. 2 Critical to this success has been advances in the knowledge and application of delivery formulations. Currently, various lipid nanoparticle (LNP) platforms are at the forefront, 3 but the encapsulation approach underpinning LNP formulations offsets the synthetic and rapid-response nature of RNA vaccines. 4 Second, limited stability of LNP formulated RNA precludes stockpiling for pandemic readiness. 5 Here, we show the development of a two-vialed approach wherein the delivery formulation, a highly stable nanostructured lipid carrier (NLC), can be manufactured and stockpiled separate from the target RNA, which is admixed prior to administration. Furthermore, specific physicochemical modifications to the NLC modulate immune responses, either enhancing or diminishing neutralizing antibody responses. We have combined this approach with a replicating viral RNA (rvRNA) encoding Zika virus (ZIKV) antigens and demonstrated a single dose as low as 10 ng can completely protect mice against a lethal ZIKV challenge, representing what might be the most potent approach to date of any Zika vaccine.