A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke.
A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke.
复制标题
DOI：
10.3389/fmolb.2021.611367
复制
发表时间：
2021
影响因子：
5
通讯作者：
Jefferies WA
中科院分区：
文献类型：
--
作者：
Eyford BA;Singh CSB;Abraham T;Munro L;Choi KB;Hill T;Hildebrandt R;Welch I;Vitalis TZ;Gabathuler R;Gordon JA;Adomat H;Guns EST;Lu CJ;Pfeifer CG;Tian MM;Jefferies WA
血脑屏障（BBB）阻碍了用于治疗中枢神经系统神经炎症（NI）的治疗剂的分布。一种12个氨基酸的肽，transcytoses血脑屏障，被称为MTfp，化学共轭siRNA创建一个新的肽-寡核苷酸共轭物（POC），直接下调NOX 4，一个基因被认为是负责缺血性中风的氧化应激。MTfp-N 0X 4 POC具有穿过完整的BBB并敲低脑中N 0X 4表达的能力。在诱导缺血性卒中后，经POC预处理的动物表现出显著较小的梗死;伴随着对神经功能恶化的保护增加和恢复改善。数据表明，MTfp可以作为纳米粒促进siRNA的BBB转胞吞作用;其中NOX-4特异性siRNA部分可以引发对中枢神经系统中负责氧化应激的基因的有效治疗性敲低。这项研究是第一个在BBB保持完整的任何CNS疾病模型中最终证明siRNA载体递送和治疗功效的研究，因此为目前对现有疗法难以治疗的各种神经病理学中的氧化应激潜在神经炎症提供了新的治疗途径。
The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of neuroinflammation (NI) of the central nervous system. A twelve-amino acid peptide that transcytoses the BBB, termed MTfp, was chemically conjugated to siRNA to create a novel peptide-oligonucleotide conjugate (POC), directed to downregulate NOX4, a gene thought responsible for oxidative stress in ischemic stroke. The MTfp-NOX4 POC has the ability to cross the intact BBB and knockdown NOX4 expression in the brain. Following induction of ischemic stroke, animals pretreated with the POC exhibited significantly smaller infarcts; accompanied by increased protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp can act as a nanomule to facilitate BBB transcytosis of siRNAs; where the NOX-4 specific siRNA moiety can elicit effective therapeutic knockdown of a gene responsible for oxidative stress in the central nervous system. This study is the first to conclusively demonstrate both siRNA-carrier delivery and therapeutic efficacy in any CNS disease model where the BBB remains intact and thus offers new avenues for potential treatments of oxidative stress underlying neuroinflammation in a variety of neuropathologies that are currently refractory to existing therapies.