Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Frank W. LoGerfo Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA.
J Transl Med. 2017 Jul 28;15(1):164. doi: 10.1186/s12967-017-1270-0.
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.
心血管疾病仍然是一个主要的医疗保健挑战。在过去的几十年中，人们对各种血管疾病病因的潜在机制有了很大的了解。这包括 microRNAs 的贡献，内源性非编码 RNA 分子，已知它们极大地影响基因表达。此外，短干扰 RNA 已被确立为一种暂时影响基因表达的机制。本文讨论了设计针对血管疾病的 RNA 干扰治疗策略所面临的挑战。尽管在医学和外科治疗方面取得了进展，但动脉粥样硬化（ATH）、主动脉瘤（AA）仍然与高发病率和死亡率相关。此外，内膜增生（IH）仍然是静脉和假体旁路移植失败的主要原因。所有这三种疾病的发病机制都包括内皮细胞（EC）的激活和血管平滑肌细胞（VSMC）的去分化。RNA 干扰是一种很有前途的技术，可用于沉默导致 ATH、AA 或 IH 的基因。成功将 RNAi 递送到血管壁面临多种障碍。这些障碍包括针对特定细胞的 RNAi 靶向递送的挑战、解剖学障碍，如动脉壁的基底膜、弹性层、多层 VSMC 以及外膜组织。另一个主要的决策点是递送途径和潜在的转染方法。已经描述了大量的转染试剂和辅助剂，它们具有不同的功效和副作用。RNAi 治疗的时间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。
尽管多项临床前研究报告了 RNAi 递送到血管壁的令人鼓舞的结果，但仍需观察是否单个靶标足以在人类受损的血管壁中实现临床所需的变化。可能需要同时或顺序沉默多个协同作用的靶基因。在针对特定细胞的 RNAi 递送上已经取得了一些进展，但仍然缺乏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良影响也是需要解决的挑战。临床医生、遗传学家、生物学家以及化学和医学工程师之间需要密切合作，为各种类型的血管疾病提供定制的治疗方法。
