*Purpose: Our data introduce APP-103 as a novel, non-toxic and site-activating therapeutic approach that effectively ameliorates the consequences of ischemia/reperfusion injury in solid organ transplantation.

*Methods: A key event driving inflammatory responses in ischemia/reperfusion injury (IRI) in alloimmunity and transplant outcomes is the burst of reactive oxygen species. Here, we used two IRI models to evaluate the therapeutic properties of APP-103 that exhibits high sensitivity and specificity towards the production of H₂O₂. APP-103 is uniquely both an antioxidant and anti-inflammatory product mitigating IRI prior to downstream alloimmune activation and the initiation of fibrotic processes. We demonstrate that APP-103 is safe, effectively promotes kidney function following IRI, and continued preclinical development is ongoing with anticipation of clinical entrance in renal transplantation in the mitigation of delayed graft function (DGF).

*Results: In a warm ischemia model, IRI was induced in the rats by clamping the left renal pedicle for 45 minutes followed by reperfusion. Control animals exhibited a dramatic increase in serum creatinine (SCrea) levels by 24 h, while animals treated with a single dose APP-103 (3 mg/kg) 10 minutes prior to IRI induction showed a significantly reduced SCrea levels. Histological analysis confirmed that treated animals were protected against IRI-induced tissue injuries. We next created a syngeneic kidney transplantation model and analyzed the therapeutic impact of APP-103 with a cold ischemia time (CIT) of 6 h. APP-103 or phosphate buffer saline (PBS) was administered IV at 15 mg/kg 1 h prior to injury and after + 2 h. Treatment with APP-103 significantly reduced SCre levels on post-operative day 1 (1.39±0.15 vs. 2.16±0.27, p=0.019). Histopathology assessment of the transplanted kidney grafts revealed tubular injury and fibrosis with extensive chronic tubule-interstitial changes, dilation of tubules, diffuse interstitial fibrosis only in vehicle-treated animals. Mechanistically, we analyzed a reduction in dihydroethidium (DHE) staining, a semi-quantitative oxidative stress indicator in the transplanted kidneys of APP-103 treated animals. In addition to a reduction in antioxidant species, kidneys from APP-103 treated animals demonstrated reduced intragraft mRNA expression of relevant pro-inflammatory cytokines.

*Conclusions: These data suggest that APP-103 represses ROS leading to a reduction of proinflammatory cytokines and improved functional graft outcomes. Thus, our results demonstrate in clinically relevant models that APP-103 alleviates IRI-associated pro-inflammatory responses by targeting the effects of H2O2.

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