Transvascular Delivery of Hydrophobically Modified siRNAs: Gene Silencing in the Rat Brain upon Disruption of the Blood-Brain Barrier
Transvascular Delivery of Hydrophobically Modified siRNAs: Gene Silencing in the Rat Brain upon Disruption of the Blood-Brain Barrier
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DOI：
10.1016/j.ymthe.2018.08.005
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发表时间：
2018-11-07
影响因子：
12.4
通讯作者：
Khvorova, Anastasia
中科院分区：
文献类型：
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作者：
Godinho, Bruno M. D. C.;Henninger, Nils;Khvorova, Anastasia
有效的经血管输送治疗性寡核苷酸到大脑是基因沉默技术发展的主要障碍，用于治疗遗传定义的神经系统疾病。由于血脑屏障（BBB）的低渗透性和这些药物从血液中的快速清除动力学，全身给药后向大脑的分布受到阻碍。在这里，我们表明血脑屏障的短暂渗透破坏使疏水修饰的小干扰RNA （hsiRNA）通过血管传递到大鼠大脑。在颈动脉内给予25%甘露醇和与磷酸胆碱-二十二碳己酸（PC-DHA）结合的hrna可导致PC-DHA- hrna在大脑内广泛的同侧分布。PC-DHA偶联使sirna保留在靠近脑血管的薄壁组织中，并使神经元和星形胶质细胞主动内化。此外，在给药后1周，经血管递送pc - dha - hsirna可使纹状体（55%）、海马（51%）、体感皮层（52%）、运动皮层（37%）和丘脑（33%）的Htt mRNA沉默。除了血脑屏障渗透破坏引起的轻度胶质瘤外，pc - dha - hsirna的经血管传递与神经毒性无关。总之，这些发现提供了概念证明，暂时破坏血脑屏障是将治疗性寡核苷酸输送到大脑的有效策略。
Effective transvascular delivery of therapeutic oligonucleotides to the brain presents a major hurdle to the development of gene silencing technologies for treatment of genetically defined neurological disorders. Distribution to the brain after systemic administrations is hampered by the low permeability of the blood-brain barrier (BBB) and the rapid clearance kinetics of these drugs from the blood. Here we show that transient osmotic disruption of the BBB enables transvascular delivery of hydrophobically modified small interfering RNA (hsiRNA) to the rat brain. Intracarotid administration of 25% mannitol and hsiRNA conjugated to phosphocholine-docosahexanoic acid (PC-DHA) resulted in broad ipsilateral distribution of PC-DHA-hsiRNAs in the brain. PC-DHA conjugation enables hsiRNA retention in the parenchyma proximal to the brain vasculature and enabled active internalization by neurons and astrocytes. Moreover, transvascular delivery of PC-DHA-hsiRNAs effected Htt mRNA silencing in the striatum (55%), hippocampus (51%), somatosensory cortex (52%), motor cortex (37%), and thalamus (33%) 1 week after administration. Aside from mild gliosis induced by osmotic disruption of the BBB, transvascular delivery of PC-DHA-hsiRNAs was not associated with neurotoxicity. Together, these findings provide proof-of-concept that temporary disruption of the BBB is an effective strategy for the delivery of therapeutic oligonucleotides to the brain.