Autosomal dominant polycystic kidney disease(ADPKD) is a common genetic kidney disease caused by mutations in either PKD1 or PKD2 genes, resulting in the presence of multiple cysts that increase in size and lead to a number of complications, including early-onset hypertension, hematuria, pain, infection, and slowly progressive chronic kidney disease that leads to end-stage renal disease by the 6th decade of life.
Dr Thomas Weimb’s group at UC Santa Barbara had shown that mTOR pathway is involved in polycystic kidney disease and that it’s inhibition reverses cyst formation in two different mice model of polycystic kidney disease, namely the Tg737orpk/orpk;TgRsq and the bpk/bpk mice (see Shilingford et al). This discovery led to two recently completed clinical trials of mTOR inhibitors, already approved as immunosuppressive agents in organ transplantation. These studies were published in the August 26, 2010 issue of New England Journal of Medicine.
The trial by Serra et al. included 100 ADPKD patients with relatively preserved renal function, treated with sirolimus or placebo for 18 months. Kidney volume and GFR were measuerd over time. The authors found no difference in kidney volume change between the sirolimus and the placebo-treated subjects and no difference in GFR between the two groups. In another study by Walz et al. published in the same issue of New England Journal of Medicine, 433 ADPKD patients were randomly assigned to receive everolimus or placebo for 24 months. In this study, everolimus resulted in a statistically non-significant slowing of the kidney volume growth compared to placebo, but no difference in GFR was observed between the two groups. The everolimus group experienced a significantly higher rate of adverse events contributing in a higher rate of discontinuation in the everolimus group.
The issues related to the use mTOR Inhibitors in ADPKD and some of the reasons for the failure of the studies by Waltz et al. and Serra et al. have been very nicely summarized in the commentary written by Terry Watnick and Gergory Germino that accompanied the publications of these two studies in same issue of the New England Journal of Medicine. A major issue with mTOR inhibitors is their toxicity at high doses, making it impossible to reach therapeutic drug levels within the kidney that have been shown in rodent models to slow the growth of cysts. To be effective, these agents must be targeted to be delivered at relatively high concentrations to the cysts within the kidney.
In a recent study published in the September 28, 2012 issue of the American Society of Nephrology, Jonathan Shillingford et al. used a folate-conjugated form of rapamycin (FC-rapa) to target renal cells. They first showed that normal tubules and cysts-lining epithelial cells from human patients and two murine models of PKD express folate receptors. Treatment of the mouse PKD models with FC-rapa reduced cyst proliferation and preserved renal function. The technology to produce folate-conjugated drugs for targeted therapy comes from Endocyte, a biotech company headquartered in Lafayette Indiana. Endocyte is developing small molecule drug conjugates for treatment of cancer, autoimmune diseases and PKD, using the folate receptor targeting technology.
A summary of this study and the collaboration with Endocyte can be found on a news release from the University of California Santa Barbara, where Dr Weimb’s laboratory is located.