Greatly Extended Subzero Ischemic Storage of Renal Allografts Using Novel Bio-inspired Next Generation Cryoprotectants

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Abstract: Organ preservation remains a daunting challenge. Organ specific ischemia windows of 4-24h greatly limit the field of organ transplantation to save lives and cause severe geographic restriction in the US and globally. However, by halting ischemic damage at the point of procurement, we could facilitate enhanced graft viability and thus faster patient recovery, drastically shorter hospital stays, and greatly diminished healthcare costs – all while tackling the biggest challenge of all – to increase the amount of available organs for transplant. The goal of this Direct-to-PhaseII SBIR proposal is to establish the pre-clinical use of XT-ViVo for the non- frozen, subzero ischemic preservation and transplantation of renal allografts leading to improved outcome in comparison to static cold storage and to render greatly extended CIT of up to 120h possible using practical storage and transport methods. Reducing damage during extended ischemia is of critical relevance to kidney transplantation. Indeed, the FDA has recognized this technology as a Breakthrough Device for up to 120h preservation of the kidney, which could lead to dynamic shifts to logistics of kidney transplantation. This project combines novel chemistry and expertise in tissue and organ preservation with world leaders in transplantation. We will apply novel cryoprotectants to high subzero temperature ischemic preservation of porcine kidneys followed by subsequent transplantation in an effort to significantly extend the ischemia window of human-sized organs in a clinically relevant model. The evaluation of innovative modalities that may transform current preservation strategies requires the use of translational animal models for reliable assessment of tissue viability and functional recovery post-preservation. Herein, we propose two primary aims of the proposed work. Advanced cryoprotectants will be synthesized and prepared into formulations as organ preservation solutions. The novel cryoprotectants will first be applied to the preservation of pig kidneys ex vivo, at subzero temperature. We will assess kidney survival, function, injury biomarkers, histology, and immunohistochemistry. This work will further asses the ability to greatly extend subzero ischemia time of the kidney up to 120h first ex vivo, and then using a widely-accepted preclinical large animal transplantation model for close clinical relevance to humans. Heterotopic kidney transplantation will be investigated after greatly extended ischemic storage on SLA-defined miniature swine. Animal survival and kidney function will be assessed similarly with a heightened level of detail at post-operative day 0, 1, 7, and 30 to assess both intermediate and long-term kidney function. Execution of the stated aims could result in a fundamental improvement in the field of organ transplantation and will aid acquisition of the final data set required prior to clearance and clinical for commercialization. The product will offer extension of the ischemia window, simplified use with minimal disruption of current practice, and strong cost competitiveness compared to the advanced organ perfusion systems being developed in the market today.