While the nephrology community awaits the outcome of a much awaited study of tolvaptan on progression of polycystic kidney disease (PCKD), a new story is emerging with very intriguing possibilities.
Previously on UKidney, we reported the disappointing outcomes with mTOR-based treatments on PCKD outcomes. While in one study with everolimus, cyst volume was blunted, renal functional loss was unchanged at the expense of greater side effects. The problem with this approach in treating PCKD is one that plagues drug therapy for many other conditions, namely that one must expose all tissues to a drug in the hope that target organ, receives adequate therapeutic exposure. The result of this strategy is overdosing the bystander organs and potentially under-dosing the target organ.
A new drug is emerging that could change all of this. FC-rapa conjugates rapamycin with folate, capitalizing on the observation that PCKD cells express high levels of folate receptors. The result is that this chimeric compound delivers a greater concentration of the drug to its target while sparing a greater number of bystander tissues. According to Dr. Jonathan M. Shillingford, who is lead investigator in this work, the uptake of FC-rapa by tissues other than the kidney would be negligible and in their studies, only kidney cells were shown to take up the chimeric compunds (see commment below). Endocyte, the company behind the congujgated rapamycin specializes in this technique which is being studied increasingly in cancer treatments as well. It is very early in the life-cycle of FC-rapa, but in one study seen in the Journal of the Amercian Society of Nephrology, the drug was highly effective at limiting cyst growth in mice while side effects are much fewer than with conventional rapamycin.
Along with the possibility of using tolvaptan to treat PCKD, this resurgence in mTOR-based treatments further brightens the horizon for patients with this disorder.