Title

Gene Silencing With siRNA (RNA Interference): A New Therapeutic Option During Ex Vivo Machine Liver Perfusion Preservation

UMMS Affiliation

Department of Surgery, Division of Organ Transplantation, UMass Memorial Medical Center; RNA Therapeutics Institute; Department of Microbiology and Physiological Systems; School of Medicine; Senior Scholars Program

Publication Date

2019-01-01

Document Type

Article

Disciplines

Analytical, Diagnostic and Therapeutic Techniques and Equipment | Genetic Phenomena | Hepatology | Nucleic Acids, Nucleotides, and Nucleosides | Surgery

Abstract

RNA interference (RNAi) is a natural process of posttranscriptional gene regulation that has raised a lot of attention culminating with the Nobel Prize in Medicine in 2006. RNAi-based therapeutics have been tested in experimental transplantation to reduce ischemia/reperfusion injury (IRI) with success. Modulation of genes of the innate immune system, as well as apoptotic genes, and those involved in the nuclear factor kappa B pathways can reduce liver injury in rodent liver pedicle clamping and transplantation models of IRI. However, in vivo use of RNAi faces limitations regarding the method of administration, uptake, selectivity, and stability. Machine perfusion preservation, a more recent alternative approach for liver preservation showing superior results to static cold preservation, could be used as a platform for gene interference therapeutics. Our group was the first to demonstrate uptake of small interfering RNA (siRNA) during liver machine preservation under both normothermic and hypothermic perfusion. Administering siRNA in the perfusion solution during ex vivo machine preservation has several advantages, including more efficient delivery, lower doses and cost-saving, and none/fewer side effects to other organs. Recently, the first RNAi drug was approved by the US Food and Drug Administration for clinical use, opening a new avenue for new drugs with different clinical applications. RNAi has the potential to have transformational therapeutic applications in several areas of medicine including transplantation. We believe that machine preservation offers great potential to be the ideal delivery method of siRNA to the liver graft, and future studies should be initiated to improve the clinical applicability of RNAi in solid organ transplantation.

DOI of Published Version

10.1002/lt.25383

Source

Liver Transpl. 2019 Jan;25(1):140-151. doi: 10.1002/lt.25383. Link to article on publisher's site

Journal/Book/Conference Title

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society

Comments

Andrew Gillooly participated in this study as a medical student as part of the Senior Scholars research program at the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

30561891

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