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Research

The current disparity between supply and demand of liver grafts has dramatically increased in the waiting time and mortality on the waiting list.

Currently, in the United States there are 16,204 people who are waiting for a liver transplant (http://optn.transplant.hrsa.gov), and the mortality in the waitlist is 14%. Most of the discarded liver grafts are from older donors, steatotic (also called fatty liver), or from non-heart beating donors (donation after cardiac death-DCD)(Abt PL, Desai NM, Crawford MD, et al. Annals of Surgery 2004; 239, 87-92., and Merion R, Pelletier SJ, Goodrich N, et al. Ann Surg 2006;244:555). Differently from brain dead donors, DCD donors grafts are removed after circulatory arrest (after withdrawal of care), and consequently these grafts suffer extensive ischemic damage.

Because of organ shortage, the use of grafts from DCD donors in US has increased from 0.95% in 2000 to 5% in 2010 (and in some regions even 10%)(http://optn.transplant.hrsa.gov).  Biliary complications in DCD organs are a major source of morbidity, graft loss, and even mortality long-term after liver transplantation.

The increased use of marginal grafts sparked interested in improving organ preservation methods. Static cold preservation has been associated with graft damage.

In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion may reduce preservation injury, allows reparative processes, improves graft viability, and potentially allowing real-time ex-vivo assessment of graft viability prior to transplantation. Machine preservation is particularly promising for life-saving transplantations (liver, heart, lungs) because viability can be assessed before transplant reducing the risk of death associated with primary-non-function.

The first human liver transplant after normothermic machine preservation was performed successfully recently by the Oxford transplant team in 2013.

The group of Dr. Robert Porte Groningen (http://www.rug.nl/staff/r.j.porte/research), to whom I have cooperated with, is one of the pioneers in machine perfusion liver preservation.   Dr. Porte Groningen group recently published their first series of discarded DCD organs with very promising application in the clinic.

We also have linked our interests of organ preservation with RNA interference.  RNA interference (RNAi) is a process through which double-stranded RNA induces the activation of endogenous cellular pathways of RNA degradation, resulting in selective and potent silencing of genes post-transcriptional, which have homology to the double strand. Much of the excitement surrounding small interfering RNA (siRNA)-mediated therapeutics arises from the fact that this approach overcomes many of the shortcomings previously experienced with alternative approaches to selective blocking of inflammatory pathways or apoptosis that use antibodies, antisense oligonucleotides or pharmacological inhibitors.

One important target in our research is cellular apoptosis which plays an important role in ischemia-reperfusion (I/R) injury during organ transplantation. Synthetic small interference RNA (siRNA) targeting P53 has proven effective to reduce renal ischemic injury and improve outcomes after transplantation. We are specifically targeting P53 because P53-mediated apoptosis is an important injury pathway in several models of ischemia.

The central focus of our study is to investigate a possible treatment with P53 siRNA during machine preservation to alleviate I/R injury in a model of rat liver reperfusion and liver transplantation. It’s important to mention that gene silencing has never been tested during machine preservation of liver grafts. We are actively proving if we can modulate the transcription of apoptotic genes during machine preservation of liver grafts, more specifically if we can decrease the rate of apoptosis of cholangiocytes of the distal bile duct.

Funding Sources

  • AASLD
  • University of Massachusetts-FDSP
  • ASTS

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