BACKGROUND
Current techniques for delivery of gene therapy, deliver the vector to the target organ and also to the systemic circulation. Targeted gene therapy aims at delivering the vector to specific and restricted cell populations, thus sparing all other cells of the unwanted effects of the gene product. Our aim was to develop an extracorporeal delivery system that would deliver a vector to our target organ, the heart, with little or no systemic leakage. Recirculation of the vector would allow even distribution of the vector through the target organ.
METHODS
A low volume extracorporeal circuit was designed using commercially available components. Using an ovine pacing induced heart failure model, the animals were placed on percutaneous extracorporeal cardiac support viaa9Fr cannula in the Left coronary artery (LCA) and a novel 9fr cannula in the Coronary Sinus (CS). After establishing cardiac support and stabilizing the subject. The vector was introduced into the circuit and recirculated for 10 minutes. At the end of this period to prevent the vector entering the systemic circulation, the circuit was emptied into a collection bag.
RESULTS
We delivered adenovirus (3.5x1012vp) encoding a pseudophosphorylated mutant PLN (AdS16EPLN, n = 9) or AdLacZ (n =6, 4.7x1012vp) to sheep with pacing induced HF. Despite 2 weeks further pacing, treatment with adenoS16E PLN significantly improved contractile function despite ongoing pacing stress and prevented ventricular remodeling in contrast to AdLacZ animals.
| Parameter (% change vs baseline) | AdS16EPLN | AdLacZ |
|---|---|---|
| LV End Diastolic Area | −14** | +13** |
| LV Ejection Fraction | −87*** | −23* |
| LV End Diastolic Pressure | −24* | +5 |
| dP/dt | +31* | −5 |
p < 0.05,
p < 0.01,
p < 0.001
CONCLUSIONS
Together the deployment of targeted delivery strategies and targeted molecular therapy has major potential for the treatment of heart failure. The V-Focus system is capable of delivering a vector to a target organ with little systemic leakage.