MO077: Systemic Therapy with a Single-Dose Kidney-Targeted Bioengineered VEGF Construct Improves Stenotic Kidney Hemodynamics in Experimental Renovascular Disease

Abstract

Abstract BACKGROUND AND AIMS We recently developed a construct of an elastin-like polypeptide fused to VEGF (ELP-VEGF) and showed its efficacy to target and protect the kidney after single systemic administration in a swine model of unilateral renovascular disease (RVD) via therapeutic angiogenesis. Despite a demonstrated renal efficacy, the possibility of off-target binding of VEGF to other organs and undesired effects exists. Thus, we augmented renal specificity by adding a kidney-targeting peptide (KTP) and showed that KTP-ELP accumulates in the kidney to a greater extent than ELP (rodents and swine). Furthermore, addition of KTP redirected ELP-VEGF, which was found at high levels in the liver, to the kidney (rodents). The current proof-of-concept study aims to define the renal therapeutic efficacy of the KTP-ELP-VEGF construct after systemic administration in RVD. METHOD RVD was induced in 12 pigs by unilateral renal artery stenosis and observed for 10 weeks. After 6 weeks, pigs were treated with a single IV dose of untargeted ELP-VEGF, KTP-ELP-VEGF (1 mg/kg, through ear vein) or placebo (n = 4 each). RBF, GFR and cortical perfusion were quantified in vivo using multi-detector CT before and 4 weeks after treatment/placebo. An additional four animals were used as normal controls. RESULTS Stenotic-kidney hemodynamics were similarly reduced in all RVD pigs 6 weeks after induction of renal artery stenosis. Administration of ELP-VEGF or KTP-ELP-VEGF led to significant improvements in RBF, GFR and cortical perfusion compared with pretreatment values, suggesting no interference with VEGF's biological activity. Notably, KTP-ELP-VEGF showed a slightly greater improvement in stenotic kidney hemodynamics than untargeted ELP-VEGF. CONCLUSION This study builds on our recent work and shows for the first time the biological activity and therapeutic efficacy of KTP-ELP-VEGF, expanding the potential of strategies using targeted renal treatments and offering the possibility of intra-renal and systemic routes of administration. The traits of KTP-ELP carriers strengthened drug-delivery strategies by minimizing off-target effects of VEGF or any other therapeutic cargo, which may help to extend applications to other forms of renal disease.