NPH RENAL & SKIN TRANSPLANTATION FOR ALLOSPECIFIC TOLERANCE INDUCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the first phase of this study (Nov 2007 - Feb 2008), we performed all transplants (n=7) without technical graft loss and were able to prolong the onset of allograft rejection in both the control (n=4) and experimental (n=3) groups compared to untreated historic controls. However, in both the control and experimental groups, we have documented side effects consistent with previously published side effects associated with rapamycin (Montgomery et. al. Am J Transplant. 2002). Given the consistent nature of the clinical symptoms, gross necropsy observations, and histological findings associated with current observed toxicities present in both groups, we ruled out Genz-29155 as the causative agent. We reduced the rapamycin dosing schedule to target decreased blood levels of 5-10 mg/ml. To ensure proper dosing modification and animal welfare, two monkeys were administered the new 'low dose rapamycin regimen' for 45 days (no transplants were performed). No clinical signs or symptoms of toxicity were observed throughout the 45 day treatment period or on gross and histological examination by necropsy (March-April 2008). As a result, a second phase of renal allograft transplants commenced, however, all remaining subjects were administered the proposed reduced rapamycin dosing, targeting blood levels of 5-10 ng/ml; control group (n=2) and experimental group (n=4). No adverse side effects were observed in either group in this second phase. Prolongation of renal allograft rejection free survival was observed in the experimental group (Genz-29155/rapamycin) compared to the control group (rapamycin/vehicle), however the reduced rapamycin dosing, required to avoid animal toxicities, was insufficient to adequately assess the synergistic potential of rapamycin with Genz-29155 to inhibit allograft rejection. In conclusion, both the PI and Genzyme Corp decided that this non-human primate renal allograft model was not sufficient to continue the investigation and pre-clinical development of Genz-29155 with rapamycin.