Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice.
Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice.
复制标题
己糖增强肌营养不良蛋白缺陷 mdx 小鼠的寡核苷酸递送和外显子跳跃
DOI：
10.1038/ncomms10981
复制
发表时间：
2016-03-11
影响因子：
16.6
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Han G;Gu B;Cao L;Gao X;Wang Q;Seow Y;Zhang N;Wood MJ;Yin H
基于碳水化合物的输注溶液在诊所中广泛使用。 GF）制定潜在的PMO活性，完全纠正异常DMD转录本，恢复骨骼肌中的肌营养不良蛋白水平，并实现功能救援没有可检测的毒性，这是由于GF介导的PMO摄取的增强，我们证明了PMO细胞的摄取是能量的，而GF代谢的ATP有助于增强肌肉的PMO的细胞摄取证明GF通过在MDX小鼠中复制细胞能量存储来增强PMO活性。己糖介导的寡核苷酸的递送，对DMD外显子滑水疗法的发展具有重要意义。
外显子的疗法（例如全身性i.v）正在探索吗？
Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD)mdxmice. We identify a glucose–fructose (GF) formulation that potentiates PMO activity, completely corrects aberrantDmdtranscripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions inmdxmice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy.