Kidney transplantation is the most effective therapeutic modality for end-stage renal disease. Given the increasing demand for donor kidneys, more centers today are transplanting kidneys that were previously considered unsuitable. Extended donor kidneys include kidneys from non-heart-beating donors, aged donors, donors with mild-to-moderate hypertension, or kidneys subjected to prolonged cold ischemia and exhibiting increased ischemia-normothermic reperfusion injury and delayed graft function, therefore necessitating dialysis in the recipient. Hepatocyte growth factor (HGF), also known as scatter factor (CF), is a renotrophic growth factor that exerts tissue protective and tissue reparative effects. Several studies have demonstrated beneficial effects associated with HGF treatment in experimental models of renal ischemia-reperfusion injury and renal transplantation, suggesting that HGF administration represents a therapeutic strategy to reduce the incidence and/or duration of DGF. Unfortunate clinical application of gene or protein therapies, are limited by immune- mediated responses, cost-prohibitive production schemes and relatively short-half life of the protein in vivo. Small molecule mimetics of bioactive proteins that recapitulate the desirable activity of the full-length protein hold significant promise in overcoming these drawbacks of gene- or protein-based therapeutics. Funded by the NIH SBIR program, and using a product discovery engine comprising phage display, 3- dimensional molecular modeling, protein chemistry and preclinical biology, we have identified BB3, a small molecule HGF mimetic. BB3 activates the SF/HGF receptor, c-Met, and has recapitulated the bioactivity of HGF in every assay tested thus far. Our SBIR Phase I and II studies indicate that the BB3 exerts cytoprotective effects, mediated, in part, via increased nitric oxide production, upregulation of anti-oxidant defenses, and inactivation of pro-apoptotic proteins. In in vivo models of renal ischemia-reperfusion injury, treatment with BB3 attenuates renal cell death and improves renal function. Consistent with the delayed postischemic expression of the SF/HGF receptor c-Met, treatment with BB3 24 hr following renal ischemia- reperfusion improves urine output, attenuates renal dysfunction and reduces mortality. Importantly, in a canine model of renal ischemia-reperfusion injury (conducted independently by Dr. Martin Mangino, Virginia Commonwealth University), BB3 treatment 24 hr following renal ischemia-reperfusion improves renal function. From a clinical development perspective, a Phase I clinical trial evaluating acute safety of systemically administered BB3 in healthy volunteers has been completed;no dose-limiting toxicity was observed. In addition, a Phase Ib clinical trial evaluating pharmacokinetics and safety of BB3 in stable adult patients on chronic hemodialysis has also been completed. BB3 pharmacokinetics and metabolite profile in this cohort is no different than that observed in healthy volunteers and the drug is well-tolerated. Based on these results, the present SBIR Phase II competing renewal is designed to conduct a pilot Phase IIa study evaluating safety and efficacy of BB3 in patients who have undergone renal transplantation and subsequently presented with DGF defined by poor renal function requiring dialysis.
A small molecule organ protective agent has significant clinical potential in renal transplantation.
|Tian, Tao; Lindell, Susanne L; Henderson, Scott C et al. (2009) Protective effects of ezrin on cold storage preservation injury in the pig kidney proximal tubular epithelial cell line (LLC-PK1). Transplantation 87:1488-96|