Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

• Published in: Journal of the American Society of Nephrology Vol. 23; no. 10; pp. 1674 - 1681
• Main Authors: SHILLINGFORD, Jonathan M, LEAMON, Christopher P, VLAHOV, Lontcho R, WEIMBS, Thomas
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.10.2012
• Subjects: Animals; Basic Research; Biological and medical sciences; Cell Line; Disease Models, Animal; Endocytosis; Folate Receptors, GPI-Anchored - metabolism; Folic Acid - analogs & derivatives; Folic Acid - therapeutic use; Humans; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Malformations of the urinary system; Medical sciences; Mice; Nephrology. Urinary tract diseases; Polycystic Kidney, Autosomal Dominant - drug therapy; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Signal Transduction - drug effects; Sirolimus - analogs & derivatives; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases - metabolism; Kidney disease; Antineoplastic agent; Nephrology; Urinary system disease; Prognosis; Sirolimus; Polycystic kidney; Lactone; Macrolide; Folate; Urology; Macrocycle; Genetic disease; Antibiotic; Cyst; Evolution; Protein synthesis inhibitor; Benign neoplasm; Immunosuppressive agent; Antibacterial agent; Slow disease
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2012040367

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.