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

点击翻译按钮获取中文摘要

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.