Immunosuppressive Donor Organ Preservation Solution


Inventors have developed a pH sensitive, targeted micelle nanoparticle for the delivery of immunosuppressive agents directly to a donor organ endothelium prior to transplantation as an additive constituent of standard organ preservation solutions. The device will be engineered in such a way as to enable it to penetrate endothelial cells (ECs) to protect them from ischemia reperfusion injury and also promote endothelial tolerance. In this format, the device is designed so that it can be used in multiple organ preservation solutions, so that it can have a broad application to all solid organ transplants.


Studies show that the TRaM is approximately 10nm in diameter and undergoes successful internalization in Human Umbilical Vein EC (HUVEC). Uptake efficiency of TRaM nanoparticles was improved with the addition of a targeting moiety. Additionally, the TRaM therapy is able to downregulate both mouse cardiac endothelial cells (MCEC) and HUVEC production and the release of pro-inflammatory cytokines, IL-6 and IL-8 in normal oxygen tension and hypoxic conditions. Inventors have also been able to demonstrate a dose-dependent uptake of TRaM therapy into biologic tissues ex vivo. All of these results demonstrate the feasibility of targeted drug delivery in transplantation, with the potential for conferring local immunosuppressive effects without systemic consequences while also dampening EC injury response.


Overview: Transplantation is a widely accepted and highly successful therapy for end-stage organ disease. While success rates and survival have risen steadily due largely to improved immunosuppression regimes, there is a growing appreciation that factors that occur early in the life of the graft significantly affect long-term survival. The donor organ is exposed to a series of injurious events prior to and during the transplant operative period, such as brain death, cold storage, cold and warm ischemia reperfusion. These events cause damage and immunologically prime the donor organ for allo-immune recognition.


Techniques for organ preservation serve to minimize this damage to promote optimal graft survival and function. Damage to donor organs prior to transplantation occurs in 2 main phases. The first (cold ischemic) phase, occurs when the organ is flushed in situ, then procured and preserved in a static or pulsatile hypothermic state prior to transplantation into the recipient. The second (warm ischemic) phase includes the time from organ removal from the preservation solution to the time it is sewn into the organ recipient.

As most transplanted organs are harvested from deceased donors, the organ must inevitably be stored until it can be transplanted into a suitable recipient. The donor and recipient are often in different locations (this can occur even when organs are harvested from living donors) and timing is critical while the donor organ is transported to the hospital where the recipient is being prepared for transplantation. Acceptable preservation times vary with the different organs. For example, most surgeons prefer to transplant heart and lungs within 5 hours of removal while kidneys can safely be stored for 24-48 hours, but earlier transplantation is preferred. Most pancreas transplants are performed after 5-15 hours of preservation. Liver transplants usually are performed within 6-12 hours. Over the last 20 years, a number of methods and solutions have been developed to preserve donor organs for transplantation. Collins et al. first introduced the simple cold storage technique to store and transport kidneys up to 30 hours. The development of the University of Wisconsin cold storage solution (UW-CSS) in 1986 improved organ preservation and resulted in a better understanding in preservation related injury. Various preservation solutions exist, each substantially different in their composition, but the purposes of each are similar: to prevent cellular edema, delay cell destruction, maintain organ metabolic potential, and maximize organ function after perfusion is reestablished. Commonly used solutions include: University of Wisconsin (UW) solution, Kyoto ET Solution, Celsior Solution, Phosphate Buffered Sucrose Solution, Bretschneider Histidine Tryptophan Ketoglutarate (HTK) Solution, Ross-Marshall Citrate Solution, Euro-Collins Solutions, and Perferdex. Different solutions are used for different organs, such as Perfedex for the lung. In addition, different solutions are preferred at different institutions.


The most widely utilized preservation solution is the University of Wisconsin (UW) solution, which was developed for liver, kidney, and pancreas preservations. It is considered the standard for renal, pancreas, and hepatic preservation, effectively extending the ischemic time for kidneys, pancreas and livers and allowing them to be transported considerable distances to waiting recipients. However, the composition of the solution is complex and the components of the solution, as with the other aforementioned solutions, are utilized to prevent cellular edema, cell destruction, maintain organ metabolic potential, and to maximize organ function after perfusion is reestablished. They do nothing to modulate the immunological injury suffered as a consequence of organ donation nor do they prepare the donor organ for the oncoming immunological attack by the recipient’s immune system.


Central to these immunological insults is the activation of donor endothelial cells (ECs) that, upon brain death, organ procurement, organ preservation, and reperfusion, promotes inflammation, cytokine and chemokine release and is central to the programming of recipient immune cells. It is appreciated that modulation of the endothelium prior to transplantation may improve graft outcomes. Recent studies have shown that treatment of ECs in vitro with the mTOR inhibitor rapamycin, an immunosuppressive drug used clinically, can render ECs tolerogenic. Pre-treatment of EC with rapamycin reduced proliferation of allo-reactive memory T cells, reduced cytokine production, reduced EC activation, and further promoted the differentiation of T regulatory cells in an EC/T cell co-culture system. These elegant studies demonstrate that pre-operative rapamycin therapy provides protection from EC-mediated immune injury. We have capitalized on these unique findings and have developed a bioengineering solution to deliver rapamycin to the donor organ ECs, by the addition of endothelial Targeted Rapamycin Micelles (TRaM) to standard organ preservation solutions.  We have shown that TRaM improves cellular penetration, as compared to untargeted rapamycin micelles (RaM), inhibits EC cytokine production, and significantly reduces MHC expression, as compared to free rapamycin drug or RaM, in in vitro models.


Currently available preservation solutions aim to stabilize organ metabolism, improve cell ion exchange, and improve cell membrane integrity, thereby facilitating prolonged organ storage, to allow for donor organ transportation. None of the currently available organ preservation solutions provide protection from inflammation or load immunosuppressive drugs into the donor organ prior to transplantation.


Therefore, the addition of TRaM to standard organ preservation solutions will prevent donor organ EC activation, cytokine release, impair immune co-stimulation, and thereby reduce graft injury. The use of such an additive to a standard preservation solution will lead to the development of a first-in-class priority preservation solution for broad application in all solid organ transplants.


Applications: Micelle delivery of immunosuppressive agents

Advantages:  Targeted nanoparticle system prevents donor organ endothelial cell activation, cytokine release, impairs immune co-stimulation, and thereby reduces graft injury.

Key Words: Organ transplant, transplantation, nanoparticle, micelle, endothelial cells, cytokines, reperfusion injury, rapamycin, preservation solution, organ storage, immunosuppression


Publication: Nadig, Satish N., et al. "Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity." RSC Advances 5.54 (2015): 43552-43562.


Inventors: Satish Nadig, Carl Atkinson, Ann-Marie Broome

Patent Status: PCT Application, PCT/US2016/39315, Filed 06/24/2016

MUSC-FRD Technology ID: P1577


Licensing Status: This technology is currently licensed to MUSC startup, ToleRaM. Please contact the FRD to be put in touch with ToleRaM.


Patent Information:
For Information, Contact:
Scott Davis
Sr Licensing Manager
MUSC Foundation for Research Development
Satish Nadig
Carl Atkinson
Ann-Marie Broome
Suraj Dixit
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