Leveraging the Highly Active Metabolite of Pioglitazone as a Scaffold for a Novel Non-Immunosuppressive Therapy for Childhood Nephrotic Syndrome.

Project Summary There are no FDA-approved drugs for Childhood Nephrotic Syndrome (NS). In NS, the kidney’s podocytes are injured, causing protein to leak into the urine. Patients typically receive steroids and must cope with the accompanying toxic side effects that can be particularly harmful for a pediatric population: growth retardation, delayed puberty, increased risk of infections, metabolic disruptions, mood and behavioral changes, and high blood pressure. In the case of complicated NS where steroids are less effective, patients receive additional immunosuppressive therapies that are only partially effective and cause additional serious side effects. The most serious side effects from steroids and other NS treatments are due to their immunosuppressive nature. Our prior research identified nuclear receptors of the kidney’s podocytes to be an alternative route for protecting the podocytes from injury and restoring the urine protein levels to a normal level. Using a medicinal chemistry approach, we designed the lead compounds in the CBP-002 program, which target a nuclear receptor agonist to the kidney. Preliminary data shows a 4x targeting to the kidney and favorable pharmacokinetics. However, recent evidence suggests that using the metabolite of this agonist could generate a more potent and less clinically variable drug. Our working hypothesis is that a carefully designed prodrug of this agonist metabolite (racemate or stereoisomer) can be targeted to preferentially accumulate in the kidney, abrogating serious side effects while maintaining or improving efficacy. Yet, the major metabolite and its stereoisomers lack full characterization, and it is unknown how the potential binding and functional differences will impact their downstream effects in NS. Thus, we propose the following Specific Aims to better characterize the metabolite: Aim 1: Perform in vitro studies of human podocytes to directly compare the protective effects of racemate agonist metabolite and its stereoisomers vs. parent agonist, benchmarking against steroids. Aim 2: Perform in vivo studies in a PAN NS animal model to directly compare the abilities of racemate or stereoisomers of agonist metabolite to reduce proteinuria compared vs. parent agonist vs. steroids. Aim 3: Compare isolated glomerular transcriptomes among PAN-NS rats with proteinuria reduction induced by the agonist metabolite vs. parent agonist vs. steroids. The in vitro and in vivo studies will identify which active moiety should be included in the nominated Drug Candidate for IND-enabling studies and greatly accelerate its translation to real clinical value for children with NS. The team leading this effort has extensive expertise in podocyte biology, NS, and drug development in rare kidney diseases. The team is joined by significant collaborators and consultants to successfully execute the proposed research plan.