A couple of years ago, it was noted that mTOR inhibitorsslowed the growth of cysts in animal models of Polycystic Kidney Disease. Althoughthe activity of mTOR is minimal in normal renal epithelial cells, in cystepithelial cells, expression is markedly increased. At the time, there wasunderstandably a lot of excitement about this and the potential for a role forrapamycin for treating patients with PCKD. (We got in on this ourselves and hadtwo posts from Nate and Conall about this possible therapeutic pathway) Unfortunately,the clinical studies were not very impressive and the excitement has sincefaded somewhat. One of the reasons put forward for why it was ineffective wasthat the doses were inadequate. The dose of rapamycin needed to suppress cystgrowth in mice was far higher than was tolerable for humans. Anyone who hasused rapamycin in transplant recipients knows about the side-effect profilewhich prevents many people from taking the drug,An article was just published in JASN which raises thepossibility that rapamycin could be used in higher doses than previouslythought possible. The folate receptor is selectively expressed on cancer cellsand renal epithelial cells. As a result, there has been some work done oncombining drugs with folate to increase the specificity of drug delivery,particularly chemotherapeutic agents and thus limiting toxicity. The beauty ofthis is that folic acid is taken up into most cells by an alternative pathwayand this pathway is not available to conjugated folate. In this study, theauthors conjugated rapamycin to folate and gave it to mice with PKD. Theyshowed that it was effective both at reducing expression of downstream targetsof mTOR and slowing cyst growth. This suggests that the combined compound couldbe given in large doses to humans with PKD and offer targeted therapy with lesschance of significant extra-renal side effects.
Photo from the University of Indiana website
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