Renal Therapeutic Angiogenesis Using the Novel Biologic ELP-VEGF

Abstract.
Chronic kidney disease (CKD) is a progressive disorder affecting almost 14% of the general population, and
this disease has shown a relentless growth over the past 2 decades. Patients with CKD have higher rates of
hospitalization, greater mortality, shorter life expectancy, and their healthcare costs are up to 5 times more
expensive than non-CKD patients. Thus, treatments to slow, halt, or reverse the progression of CKD could have
a significant financial and clinical impact. Chronic renal vascular disease (RVD), often associated with renal
artery stenosis, can deteriorate renal function and lead to CKD and end-stage renal disease in up to 15% of
patients. Despite the availability of treatments for RVD including drugs and percutaneous transluminal renal
angioplasty, renal function does not improve or even deteriorates in over half of the patients undergoing these
treatments. Leflore Technologies has developed a biopolymer-stabilized form of vascular endothelial growth
factor (VEGF) with high renal binding. Leflore Technology’s overall strategy is to use the biopolymer-VEGF
fusion for therapeutic angiogenesis to restore renal microvasculature and improve renal function in RVD and/or
CKD. During the Phase I portion of this STTR, non-GLP efficacy and toxicity testing were conducted with the
biopolymer-fused VEGF. Using a swine model of renal artery stenosis – induced RVD, angioplasty and stenting
with or without therapeutic renal angiogenesis using our biopolymer-stabilized VEGF was tested in a preclinical
trial. In the treatment arm, renal function and renal vascular density were significantly improved, and histological
markers of renal injury were reduced, relative to angioplasty and stenting alone. We also performed a dose-
escalating toxicology study in rats, which demonstrated that the biopolymer-stabilized VEGF induced no
significant side-effects at doses up to 100 times the planned therapeutic dose. The proposed Phase II studies
will advance the lead agent through cGMP manufacturing; chemistry, manufacturing and controls testing; and
expanded preclinical IND-enabling GLP toxicology. The planned studies will also extend our prior efficacy
studies by testing in animals with progressively more severe renal disease, with longer follow-ups, and using
multiple rodent models of CKD caused by diabetes or hypertension as well as extended studies in our
translational swine model of CKD to expand the potential target market beyond RVD treated with stenting to
chronic kidney disease as a whole.

Grant Number: 5R42DK109737-04
NIH Institute/Center: NIH
Principal Investigator: Gene Bidwell