RNAi therapy to the wall of arteries and veins: anatomical, physiologic, and pharmacological considerations.
RNAi therapy to the wall of arteries and veins: anatomical, physiologic, and pharmacological considerations.
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DOI：
10.1186/s12967-017-1270-0
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发表时间：
2017-07-28
影响因子：
7.4
通讯作者：
LoGerfo FW
中科院分区：
文献类型：
--
作者：
Nabzdyk CS;Pradhan-Nabzdyk L;LoGerfo FW
心血管疾病仍然是一个重大的卫生保健挑战。在过去的几十年里，关于各自血管疾病病因学的潜在机制的知识已经大大扩展。这包括microRNA的贡献，内源性非编码RNA分子，已知极大地影响基因表达。此外，短干扰RNA已被确立为暂时影响基因表达的机制。这篇综述讨论了与设计用于调节血管疾病的RNA干扰治疗策略有关的挑战。尽管内科和外科治疗取得了进展，但动脉粥样硬化（ATH）、主动脉瘤（AA）仍具有较高的发病率和死亡率。此外，内膜增生（IH）仍然是晚期静脉和人工旁路移植失败的主要原因。所有这三种实体的病理机制包括内皮细胞（EC）的活化和血管平滑肌细胞（VSMC）的去分化。RNA干扰是一种很有前途的技术，可以用来沉默基因有助于ATH，AA或IH。成功的RNAi递送到血管壁面临着多种障碍。这些挑战包括细胞特异性、靶向递送RNAi、解剖学屏障如基底膜、动脉壁中的弹性层、多层VSMC以及外膜组织的挑战。另一个主要的决定点是递送途径和潜在的转染方法。已经描述了具有不同功效和副作用的大量转染试剂和转染剂。RNAi治疗的时机和持续时间以及靶基因的选择是需要以时空方式解决的进一步相关方面。虽然多项临床前研究报告了RNAi递送至血管壁的令人鼓舞的结果，但仍有待观察的是，单一靶标是否足以在人类受损的血管壁中实现临床上期望的变化。可能有必要实现多个协同作用的靶基因的同时和/或顺序沉默。在细胞特异性RNAi递送方面已经取得了一些进展，但是仍然缺少可靠的血管细胞特异性转染策略。此外，RNAi的脱靶效应和转染剂对基因表达的不希望的效应是有待解决的挑战。需要临床医生、遗传学家、生物学家以及化学和医学工程师之间的密切合作，为各种类型的血管疾病提供量身定制的治疗方法。
Cardiovascular disease remains a major health care challenge. The knowledge about the underlying mechanisms of the respective vascular disease etiologies has greatly expanded over the last decades. This includes the contribution of microRNAs, endogenous non-coding RNA molecules, known to vastly influence gene expression. In addition, short interference RNA has been established as a mechanism to temporarily affect gene expression. This review discusses challenges relating to the design of a RNA interference therapy strategy for the modulation of vascular disease. Despite advances in medical and surgical therapies, atherosclerosis (ATH), aortic aneurysms (AA) are still associated with high morbidity and mortality. In addition, intimal hyperplasia (IH) remains a leading cause of late vein and prosthetic bypass graft failure. Pathomechanisms of all three entities include activation of endothelial cells (EC) and dedifferentiation of vascular smooth muscle cells (VSMC). RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH, AA or IH. Successful RNAi delivery to the vessel wall faces multiple obstacles. These include the challenge of cell specific, targeted delivery of RNAi, anatomical barriers such as basal membrane, elastic laminae in arterial walls, multiple layers of VSMC, as well as adventitial tissues. Another major decision point is the route of delivery and potential methods of transfection. A plethora of transfection reagents and adjuncts have been described with varying efficacies and side effects. Timing and duration of RNAi therapy as well as target gene choice are further relevant aspects that need to be addressed in a temporo-spatial fashion. While multiple preclinical studies reported encouraging results of RNAi delivery to the vascular wall, it remains to be seen if a single target can be sufficient to the achieve clinically desirable changes in the injured vascular wall in humans. It might be necessary to achieve simultaneous and/or sequential silencing of multiple, synergistically acting target genes. Some advances in cell specific RNAi delivery have been made, but a reliable vascular cell specific transfection strategy is still missing. Also, off-target effects of RNAi and unwanted effects of transfection agents on gene expression are challenges to be addressed. Close collaborative efforts between clinicians, geneticists, biologists, and chemical and medical engineers will be needed to provide tailored therapeutics for the various types of vascular diseases.
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影响因子：
64.8
作者：
Cordes KR;Sheehy NT;White MP;Berry EC;Morton SU;Muth AN;Lee TH;Miano JM;Ivey KN;Srivastava D
通讯作者：
Srivastava D
影响因子：
20.1
作者：
Climent, Montserrat;Quintavalle, Manuela;Elia, Leonardo
通讯作者：
Elia, Leonardo
影响因子：
2.2
作者：
Bools, Lindsay M.;Fisher, Richard K.;Mountain, Deidra J. H.
通讯作者：
Mountain, Deidra J. H.
DOI：
10.1073/pnas.0504934102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Drusco, A;Zanesi, N;Croce, CM
通讯作者：
Croce, CM
DOI：
10.1016/j.jamcollsurg.2006.12.029
发表时间：
2007-03-01
影响因子：
5.2
作者：
Andersen, Nicholas D.;Monahan, Thomas S.;LoGerfo, Frank W.
通讯作者：
LoGerfo, Frank W.