Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an orthologous mouse model of polycystic kidney disease

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models. However, clinical trials with mTOR inhibitors were disappointing largely due to the intolerable extrarenal side effects during long-term treatment with these drugs. Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in ADPKD patients. To overcome this problem, we previously demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and FC-rapa are similarly effective on polycystic kidneys in this model. However, FC-rapa lacks the extrarenal effects of unconjugated rapamycin, in particular immunosuppressive effects. We conclude that folate-conjugation is a promising avenue for increasing the tissue specificity of small-molecule compounds to facilitate very long-term treatment in ADPKD.

mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division

“…The great efficacy of rapamycin derivatives in several mouse models of PKD raised hope for a cure for these devastating diseases 2,3,7,66 . In human clinical trials, rapamycin derivatives blunted angiomyolipoma growth in TSC patients 67 , while the results for ADPKD were moderate or negative [68][69][70] .…”

Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease

“…FRα expression was also found to be high in renal cysts in mouse models of PKD and human ADPKD samples [11, 124], which suggested that PKD could be amenable to FR-targeting strategies. A folate-targeted form of the mTORC1 inhibitor (see above) rapamycin ( FC-rapa or EC0371 ) was developed that included a hydrophilic spacer and a self-immolative linker designed to be cleaved intracellularly to reconstitute the active drug [11].…”

“…Both, FC-rapa and unconjugated rapamycin were similarly effective in inhibiting PKD disease progression. However, FC-rapa exhibited much reduced extra-renal effects, including effects on the immune system and reduced systemic toxicity as assessed by body weight gain over time [124]. In the same study, it could also be directly demonstrated that renal cysts are accessible to folate-conjugated compounds as assessed using a novel fluorescent folate-conjugated reporter [124].…”

“…However, FC-rapa exhibited much reduced extra-renal effects, including effects on the immune system and reduced systemic toxicity as assessed by body weight gain over time [124]. In the same study, it could also be directly demonstrated that renal cysts are accessible to folate-conjugated compounds as assessed using a novel fluorescent folate-conjugated reporter [124]. This reporter was efficiently taken up by the collecting duct-derived cysts that are prevalent in the bpk mouse model [124], and FC-rapa was effective in inhibiting the growth of these cysts [11].…”

“…In the same study, it could also be directly demonstrated that renal cysts are accessible to folate-conjugated compounds as assessed using a novel fluorescent folate-conjugated reporter [124]. This reporter was efficiently taken up by the collecting duct-derived cysts that are prevalent in the bpk mouse model [124], and FC-rapa was effective in inhibiting the growth of these cysts [11]. These results indicate that the FR is expressed on collecting duct-derived cysts and not restricted to cysts that originate from proximal tubules.…”