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

通过基因治疗 CRISPR/Cas9 方法激活长非编码 RNA 以预防静脉移植失败

• 批准号: EP/X024563/1
• 负责人: Andrew Baker
• 金额: $ 16.47万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX024563%2F1
• 关键词: Activation; long; non; coding; RNA

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.

血管损伤后的病理性血管重塑是主要的未满足的临床需求。对血管沃利斯的损伤取决于环境和背景。导致这种损伤的线索可以是急性的（例如，将自体隐静脉置入冠状动脉循环-静脉移植物中），也可以是慢性的（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（vSMC）在病理性血管重塑中起着重要作用。因此，靶向vSMC的治疗方法可能对治疗CVD，特别是静脉移植失败具有重要的前景。因此，我们认为暂时恢复长的非编码RNA水平是阻断不良血管重塑的一种新的治疗方法。这在临床上很有吸引力，因为未满足临床需求，并且在手术时离体进入靶组织（即自体人隐静脉），但如果我们的电极导线数据成功，则未来在其他领域也有潜力。我们的策略对人类疾病有明确的转化范围。所描述的工作的价值主张将是几倍的;对细胞转化的进一步理解和对静脉移植失败的影响将是相当大的，并且在这种情况的潜在治疗中是一个重大的转型步骤。基因疗法的发展所要克服的障碍并非微不足道，然而，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高的可能性被广泛实施，因为它将利用静脉移植物非常适合在移植程序之前进行离体基因治疗，再加上我们专注于防止移植物中的早期病理性重塑。