**5.4.3 Vascular Endothelial Growth Factor D (VEGF-D) gene therapy**

In animal models of angioplasty induced restenosis, the delivery of adenoviral particles encoding for vascular-endothelial growth factor C to the site of vascular injury has been shown to trigger the release of nitric oxide and prostacyclin and reduce neointimal hyperplasia 199. Preliminary studies on the use of VEGF-D gene therapy (using a packaged adenoviral vector and a biodegradable local delivery device (collar) made of collagen wrapped at the venous anastomosis at the time of surgery), "Trinam®" (Ark Therapeutics; London, UK), in patients receiving AVGs, have been able to document technical feasibility and safety. A phase III study using this technology was initiated in 2009 but terminated in 2010 due to poor enrollment.

## **5.4.4 Recombinant elastase PRT-201**

PRT-201 (Proteon Therapeutics; Waltham, MA) is a recombinant pancreatic elastase topically applied at the outflow vein at the time of surgery access creation which has been shown to result in both arterial and venous dilation and an increase in AVF blood flow in experimental models 200. The clinical benefit of this approach is the potential ability to enhance AVF maturation (through rapid vascular dilation) and prevent venous stenosis in AVGs. A phase II study using this novel technology is ongoing in the United States evaluating this therapy and whether or not it improves primary patency and cumulative survival in AVG and AVF, as well as safety.

### **5.5 Endovascular stent therapy**

Endovascular vascular therapies (angioplasty or angioplasty with stent placement) remains the only true intervention available to treat vascular stenosis. The main advantage of stent therapy after angioplasty is a reduction in adverse remodeling. In dialysis access, placement

WrapTM, (Angiotech Pharmaceuticals, Inc.; Vancouver, British Columbia, Canada), was initiated to study the effectiveness and safety of this therapy on primary AVG patency compared to a standard AVG. However, this study was recently suspended in 2009 following a data safety monitoring review, due to an imbalance in the incidence of infections in one of the arms (either control or treatment). An alternative approach is the use of sirolimus eluting COLL-R® wraps (Covalon Technologies Ltd: Mississauga, Ontario, Canada). An initial Phase II study demonstrated primary unassisted AVG patency of 75%

The rationale behind the use of these wraps is that the endothelial cell (in addition to lining blood vessels) is also a "bioreactor" which produces a large number of beneficial mediators that reduces thrombosis, inflammation, stenosis, and increases lumen diameter. Initial experimental studies have documented a beneficial effect of endothelial cell loaded gel-foam wraps in porcine models of AV fistula and graft stenosis 195-198. A recent Phase II study ("V-HEALTH") was able to demonstrate technical feasibility and safety in hemodialysis patients who received a "Vascugel®" wrap loaded with treated human aortic endothelial cells at the time of AVF or AVG placement 97. A phase III multi-center randomized-controlled study using the Vascugel® (Pervasis Therapeutics, Inc., Cambridge, MA) wraps in human AVGs is

In animal models of angioplasty induced restenosis, the delivery of adenoviral particles encoding for vascular-endothelial growth factor C to the site of vascular injury has been shown to trigger the release of nitric oxide and prostacyclin and reduce neointimal hyperplasia 199. Preliminary studies on the use of VEGF-D gene therapy (using a packaged adenoviral vector and a biodegradable local delivery device (collar) made of collagen wrapped at the venous anastomosis at the time of surgery), "Trinam®" (Ark Therapeutics; London, UK), in patients receiving AVGs, have been able to document technical feasibility and safety. A phase III study using this technology was initiated in 2009 but terminated in

PRT-201 (Proteon Therapeutics; Waltham, MA) is a recombinant pancreatic elastase topically applied at the outflow vein at the time of surgery access creation which has been shown to result in both arterial and venous dilation and an increase in AVF blood flow in experimental models 200. The clinical benefit of this approach is the potential ability to enhance AVF maturation (through rapid vascular dilation) and prevent venous stenosis in AVGs. A phase II study using this novel technology is ongoing in the United States evaluating this therapy and whether or not it improves primary patency and cumulative

Endovascular vascular therapies (angioplasty or angioplasty with stent placement) remains the only true intervention available to treat vascular stenosis. The main advantage of stent therapy after angioplasty is a reduction in adverse remodeling. In dialysis access, placement

and 38% at 1 and 2 years respectively with these wraps 194.

**5.4.3 Vascular Endothelial Growth Factor D (VEGF-D) gene therapy** 

**5.4.2 Endothelial cell loaded gel foam wraps** 

currently being designed.

2010 due to poor enrollment.

**5.4.4 Recombinant elastase PRT-201** 

survival in AVG and AVF, as well as safety.

**5.5 Endovascular stent therapy** 

of bare metal stents after angioplasty compared to angioplasty 201 alone has been shown to improve primary patency 202,203. However, bare-metal stents have yielded poor results due to aggressive development of in-stent restenosis. In experimental models of dialysis access in AVGs, drug-eluting stents have shown to reduce neointimal hyperplasia and improve luminal stenosis compared to bare-metal stents 204. However, there are no clinical studies evaluating drug-eluting stents in dialysis access to date.

Stent grafts (covered stents constructed from the same material of AVGs) have received recent attention as a therapy for prevention of restenosis due to its ability to prevent elastic recoil and inability of the neointimal cells to penetrate the covered barrier. A recently published multicenter, randomized controlled, clinical trial showed stent grafts (Bard Peripheral Vascular, Tempe, AZ), placed after angioplasty, to treat venous stenosis had better primary unassisted patency compared to angioplasty alone 205. This is the only treatment to date that has shown to be effective to treat vascular access stenosis in a large, randomized, clinical trial.

### **5.6 Improving hemodynamics**

Hemodynamic sheer stresses play a significant role in development of neointimal hyperplasia 87,112,206,207. Therefore, altering the sheer stress pattern to prevent turbulent, lowflow, and low-sheer stresses could reduce the development of neointimal hyperplasia. Previous clinical data to date to support such an intervention comes from several studies evaluating cuffed AVG grafts ("Venaflo"; Bard Vascular, Tempe Arizona) 208-210. In a recent randomized control trial evaluating cuffed vs non-cuffed AVG, cuffed AVGs showed better primary patency and cumulative survival 211. Finally, results from a newly developed anastomotic implant device, "OptiflowTM" (Bioconnect Systems; Ambler, PA), to connect the artery and vein in AVFs and improve hemodynamics by providing a symmetric flow pattern, have shown a primary patency of 83% at 90 days 212. This primary patency rate was higher compared to other similarly published studies 213.

### **6. Future perspectives: new frontiers in research**

In the last decade our knowledge of vascular access dysfunction has significantly evolved. We now understand that the most common pathologic lesion seen in AVF and AVG dysfunction is aggressive venous neointimal hyperplasia, and biofilms and fibrin sheaths play a major role in CVC infection and dysfunction. In order to advance the field further, we need to further our current understanding of both the clinical and experimental pathways that result in venous neointimal hyperplasia and mechanisms that lead to biofilm and fibrin sheath production in CVCs by using the advanced technologies and tools in cellular and molecular biology, bioengineering, genomics, proteomics, and vascular imaging (ultrasound, computed tomography, and magnetic resonance imaging) 65,124,214. Finally, small and large animal models of AVF and AVG, which a number of investigators in this field have already developed 61,93,207,215-217, will play an essential role in "translating" our knowledge of pathophysiologic mechanisms in vascular access dysfunction to novel therapies for patients.

### **7. Conclusion**

The magnitude and costs of dialysis access dysfunction is clearly evident, and will only become magnified in the coming years as the prevalent dialysis population continues to

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