[1]宋军,林曹瑞,贾璐璐,等.B族维生素对肌肉萎缩小鼠PMO运输效率的影响[J].天津医科大学学报,2021,27(05):482-486.
SONG Jun,LIN Cao-rui,JIA Lu-lu,et al.Vitamin B promotes PMO drug delivery efficiency in dystrophic mice[J].Journal of Tianjin Medical University,2021,27(05):482-486.
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B族维生素对肌肉萎缩小鼠PMO运输效率的影响(PDF)
SONG Jun,LIN Cao-rui,JIA Lu-lu,et al.Vitamin B promotes PMO drug delivery efficiency in dystrophic mice[J].Journal of Tianjin Medical University,2021,27(05):482-486.
《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]
- 卷:
- 27卷
- 期数:
- 2021年05期
- 页码:
- 482-486
- 栏目:
- 基础医学
- 出版日期:
- 2021-09-10
文章信息/Info
- Title:
- Vitamin B promotes PMO drug delivery efficiency in dystrophic mice
- 文章编号:
- 1006-8147(2021)05-0482-05
- Author(s):
- SONG Jun1; LIN Cao-rui1; JIA Lu-lu1; HAN Gang2; YIN Hai-fang1
- （1. Department of cell biology，School of Basic Medical Sciences，Tianjin Medical University，Tianjin 300070，China; 2. Department of Clinical Biochemistry，School of Medical Technology，Tianjin Medical University，Tianjin 300203，China）
- Keywords:
- vitamin B12; DMD; PMO; exon-skipping
- 分类号:
- Q7
- DOI:
- -
- 文献标志码:
- A
- 摘要:
- 目的：探究B族维生素对反义寡核苷酸药物磷酸二胺吗啉代寡核苷酸（PMO）在DMD治疗中运输效率的影响以及药物安全性评价。方法：通过对成年的杜兴肌肉萎缩症（DMD）模型mdx小鼠胫骨前肌分别局部注射PMO和各种维生素的混合液，利用免疫荧光（IF）和Western印迹检测dystrophin蛋白表达情况，评估各维生素对PMO作用效果的影响；通过尾静脉注射PMO和维生素B12的混合液，相同方法检测维生素B12对PMO治疗效果的影响，同时利用苏木素-伊红组织染色（HE）技术检测组织病理情况，评估维生素B12联合PMO治疗的安全性。结果：在mdx小鼠局部给药实验中，比较不同的B族维生素对PMO药效影响时，发现维生素B12对PMO的促进效果最佳（t=8.015，P＜0.01）；随后选择维生素B12与PMO混合对mdx小鼠进行系统治疗时，相比于PMO生理盐水组，发现维生素B12能够在胫骨前肌（t=9.631，P＜0.01）和股四头肌（t=8.452，P＜0.01）上明显提高PMO的系统治疗效果，同时对mdx小鼠不产生肌肉不良反应。结论：维生素B12作为营养补充剂能够显著提高PMO在mdx小鼠上的局部治疗效果，但系统治疗效果有限，且对小鼠肌肉组织无损伤。
- Abstract:
- Objective: To investigate the effect of vitamin B on enhancing the delivery efficiency of phosphorodiamidate morpholino oligonuclcotides （PMO） in the treatment of Duchenne muscular dystrophy（DMD） and evaluate the drug safety. Methods: PMO in different vitamin B solutions or saline was injected into tibialis anterior of adult DMD model mdx mice. Immunofluorescence（IF） and Western blotting were used to measure the distribution and expression of dystrophin，and the local effect of vitamin B for PMO was evaluated. PMO in vitamin B12 solution was intravenously to evaluate the systemic effect of vitamin B12 on PMO by IF and Western blotting. Haematoxylin and eosin（HE） stain was utilized to examine the histopathological situation，and to evaluate the safety of vitamin B12 combined with PMO. Results: Local intramuscular administration experiment of mdx mice showed that vitamin B12 had the best promotion effect on PMO（t=8.015，P＜0.01） compared to the effects of different B vitamins on PMO. Systemic injection of PMO in vitamin B12 for mdx mice could significantly improve the systemic therapeutic effect of PMO on tibialis anterior（t=9.631，P＜0.01） and quadriceps muscles（t=8.452，P＜0.01） without any detectable toxicities，compared to PMO in saline groups. Conclusion: Vitamin B12 as a nutritional supplement could significantly enhance the local therapeutic effect of PMO in mdx mice，but the systemic therapeutic effect is limited，and there is no damage to the muscle tissue of mice.
参考文献/References:
[1] VAN DER PIJL E，VAN PUTTEN M，NIKS E，et al. Low dystrophin levels are insufficient to normalize the neuromuscular synaptic abnormalities of mdx mice[J]. Neuromuscul Disord，2018，28（5）：427
[2] TUFFERY-GIRAUD S，MIRO J，KOENIG M，et al. Normal and altered pre-mRNA processing in the DMD gene[J]. Hum Genet，2017， 136（9）：1155
[3] GUIRAUD S，AARTSMA-RUS A，VIEIRA N，et al. The pathogenesis and therapy of muscular dystrophies[J]. Annu Rev Genomics Hum Genet，2015，16：281
[4] 卜鑫珏，奚鑫，刘松青，等. 治疗杜兴肌肉萎缩症的新药及其开发[J]. 中国新药杂志，2020，29（2）：165
[5] MATTHEWS E，BRASSINGTON R，KUNTZER T，et al. Corticosteroids for the treatment of Duchenne muscular dystrophy[J]. Cocharne Db Syst Rev，2016（5）：CD003725
[6] PEVERELLI L，TESTOLIN S，VILLA L，et al. Histologic muscular history in steroid-treated and untreated patients with Duchenne dystrophy[J]. Neurology，2015，85（21）：1886
[7] HEIER C，DAMSKER J，YU Q，et al. VBP15，a novel anti-inflammatory and membrane-stabilizer，improves muscular dystrophy without side effects[J]. EMBO Mol Med，2013，5（10）：1569
[8] LIM K，MARUYAMA R，YOKOTA T. Eteplirsen in the treatment of Duchenne muscular dystrophy[J]. Drug Des Devel Ther，2017，11：533
[9] CIRAK S，ARECHAVALA-GOMEZA V，GUGLIERI M，et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment：an open-label，phase 2，dose-escalation study[J]. Lancet，2011，378（9791）：595
[10] HU Y，WU B，ZILLMER A，et al. Guanine analogues enhance antisense oligonucleotide-induced exon skipping in dystrophin gene in vitro and in vivo[J]. Mol Ther，2010，18（4）：812
[11] KENDALL G，MOKHONOVA E，Moran M，et al. Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy[J]. Sci Transl Med，2012，4（164）：164
[12] HAN G，GU B，CAO L，et al. Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice[J]. Nat Commun，2016，7：1098
[13] LIN C，HAN G，NING H，et al. Glycine eenhances satellite cell proliferation，cell transplantation，and oligonucleotide efficacy in dystrophic muscle[J]. Mol Ther，2020，28（5）：1339
[14] CHAWLA J，KVARNBERG D. Hydrosoluble vitamins[J]. Handb Clin Neurol，2014，120：891
[15] RAHIMOV F，KUNKEL L. The cell biology of disease：cellular and molecular mechanisms underlying muscular dystrophy[J]. J Cell Biol，2013，201（4）：499
[16] KLEIN S，PRANTL L，GEIS S，et al. Circulating serum CK level vs. muscle impairment for in situ monitoring burden of disease in mdx-mice[J]. Clin Hemorheol Microcirc，2017，65（4）：327
[17] LEWON M，PETERS C，VAN RY P，et al. Evaluation of the behavioral characteristics of the mdx mouse model of Duchenne muscular dystrophy through operant conditioning procedures[J]. Behav Processes，2017，142：8
[18] STEIN C. Eteplirsen approved for Duchenne muscular dystrophy：the FDA faces a difficult choice[J]. Mol Ther，2016，24（11）：1884
[19] ANWAR S，YOKOTA T. Golodirsen for Duchenne muscular dystrophy[J]. Drugs Today （Barc），2020，56（8）：491
[20] 宁含含，顾犇，韩刚，等. 己糖对杜兴肌肉萎缩症核酸药物Pip5e-PMO跳读活性研究[J]. 天津医科大学学报，2019，25（3）：215
[21] VOLKOV I，PRESS Y，RUDOY I. Vitamin B12 could be a "master key" in the regulation of multiple pathological processes[J]. J Nippon Med Sch，2006，73（2）：65
[22] ERFANPARAST A，Escort M，Tamaddonfard E，et al. Systemic and local peripheral injections of vitamin B12 suppressed orofacial nociception induced by formalin in rats[J]. Drug Res，2014，64（2）：85
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备注/Memo
- 备注/Memo:
-
基金项目 国家自然科学基金（81802124）；天津市自然科学基金（18JCQNJC79400）
作者简介 宋军（1995-），男，硕士在读，研究方向：基因治疗和药物运输；通信作者: 尹海芳，E-mail:haifangyin@tmu.edu.cn；韩刚，E-mail：hangang@tmu.edu.cn。
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