title: Folate-conjugated rapamycin slows progression of polycystic kidney disease.
abstract: Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor-mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose- and folate receptor-dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.
authors.affiliation: Molecular, Cellular, and Developmental Biology, University of California-Santa Barbara, CA 93106-9610, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Shillingford
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimbs
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004705:Endocytosis; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D005492:Folic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus