Activation of long non-coding RNA by a gene therapy CRISPR/Cas9 approach to prevent vein graft failure

血管损伤后的病理性血管重构是目前尚未满足的主要临床需求。血管壁损伤与环境和环境有关。导致这种损伤的线索可能是急性的（例如，在将自体隐静脉植入冠状动脉循环的情况下——静脉移植），也可能是慢性的（在发生动脉粥样硬化或肺动脉高压的情况下）。血管平滑肌细胞在病理性血管重构中起着至关重要的作用。因此，针对vSMCs的治疗方法可能对治疗CVD，特别是静脉移植衰竭具有重要的前景。因此，我们建议瞬时恢复长链非编码RNA水平是阻断不良血管重构的新治疗方法。由于在手术时未满足临床需求和离体进入目标组织（即自体人隐静脉），这在临床上具有吸引力，但如果我们的领先数据成功，未来在其他领域也有潜力。我们的战略对人类疾病具有明确的转化作用。所描述的工作的价值主张将是几倍；进一步了解细胞转移及其对静脉移植失败的影响将是相当重要的，并且是这种疾病潜在治疗的重要转变步骤。在开发基因疗法的过程中，需要克服的障碍并非微不足道，但是，治愈或至少停止症状和延长生命的潜力超过了成本效益比。如果成功，我们提出的方法将有更大的可能性被大规模实施，因为它将利用静脉移植物在移植手术前非常适合体外基因治疗的优势，再加上我们对预防移植物早期病理重塑的关注。

Pathological vascular remodelling following injury to the vasculature is of major unmet clinical need. Injury to the vessel wallis both environment- and context-dependent. Cues that drive such insults can be either acute (for example in the context ofplacing an autologous saphenous vein into the coronary arterial circulation - vein graft) or more chronic (in the cases ofdeveloping atherosclerosis or pulmonary hypertension). Vascular smooth muscle cells (vSMCs) have a crucial role inpathological vascular remodelling. Therefore, a therapeutic approach of targeting vSMCs may hold significant promise fortreating CVD, particularly vein graft failure. We therefore propose that transiently restoring a long non-coding RNA level is anovel therapeutic approach to block adverse vascular remodelling. This is clinically appealing due to the unmet clinical needand ex vivo access to the target tissue (i.e. autologous human saphenous vein) at the time of surgery, but with potential inother areas in the future should our lead data be successful. Our strategy has clear translational reach to human disease.The value proposition of the work described will be several fold; the further understanding of cell transitions and the impactthis has on vein graft failure will be considerable and a significant transformational step change in a potential treatment ofthis condition. The hurdles to overcome in the development of a gene therapy are not insignificant, however, the potential forcure or at least cessation of symptoms and life prolongation outweigh the cost benefit ratio. If successful, our proposedapproach will have a higher likelihood of being implemented at a wide scale, since it would take advantage of the vein graftsbeing ideally suited for ex vivo gene therapy before the grafting procedure coupled to our focus on preventing earlypathological remodelling in the graft.