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

Pathological vascular remodelling following injury to the vasculature is of major unmet clinical need. Injury to the vessel wall
is both environment- and context-dependent. Cues that drive such insults can be either acute (for example in the context of
placing an autologous saphenous vein into the coronary arterial circulation - vein graft) or more chronic (in the cases of
developing atherosclerosis or pulmonary hypertension). Vascular smooth muscle cells (vSMCs) have a crucial role in
pathological vascular remodelling. Therefore, a therapeutic approach of targeting vSMCs may hold significant promise for
treating CVD, particularly vein graft failure. We therefore propose that transiently restoring a long non-coding RNA level is a
novel therapeutic approach to block adverse vascular remodelling. This is clinically appealing due to the unmet clinical need
and ex vivo access to the target tissue (i.e. autologous human saphenous vein) at the time of surgery, but with potential in
other 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 impact
this has on vein graft failure will be considerable and a significant transformational step change in a potential treatment of
this condition. The hurdles to overcome in the development of a gene therapy are not insignificant, however, the potential for
cure or at least cessation of symptoms and life prolongation outweigh the cost benefit ratio. If successful, our proposed
approach will have a higher likelihood of being implemented at a wide scale, since it would take advantage of the vein grafts
being ideally suited for ex vivo gene therapy before the grafting procedure coupled to our focus on preventing early
pathological remodelling in the graft.