Therapeutic alteration of transplantable tissues through
The present invention, at least in part, relates to the discovery of efficacious delivery of an RNAi agent (in preferred aspects of the invention, an siRNA) to a transplantable tissue. Organ rejection, transplantation-mediated transmission of viral infection, and triggering of apoptosis in transplanted tissues can each be minimized by the methods and compositions of the instant invention. The RNAi agent(s) of the instant invention can be delivered as “naked” molecules, or using liposomal and other modes of delivery, to transplantable tissues. Such delivery can occur via perfusion of the RNAi agent in solution through the vasculature of a whole or partial organ; or tissues including transplantable cells and cell lines may be bathed, injected or otherwise treated with RNAi agents. Preferred transplantable tissues include, for example, pancreas, liver, kidney, heart, lung, and all cells and cell lines derived from such tissues (e.g., pancreatic islet cells that may, e.g., be transplanted as a treated population).
1. A method of treating a subject organ at risk of apoptosis-induced ischemic injury, the method comprising administering to the subject organ an RNAi agent capable of downmodulating ischemia-induced apoptosis, wherein the RNAi agent comprises a sense strand and an anti-sense strand, wherein the anti-sense strand is sufficiently complementary to p53 RNA to reduce the production of p53 via RNA-induced silencing complex (RISC) so as to counter apoptosis-induced ischemic injury in the organ, and wherein said administering comprises injecting the RNAi agent.
2. The method of claim 1 , wherein the organ is a kidney, liver, pancreas, islet cell, heart, or lung.
3. The method of claim 1 , wherein the RNAi agent is in a solution that comprises either saline or an immunosuppressant.
4. The method of claim 1 , wherein the RNAi agent is an siRNA molecule.
5. The method of claim 1 , wherein the RNAi agent is an shRNA molecule.
6. The method of claim 1 , wherein the RNAi agent comprises an oligonucleotide comprising a modification to a 2′-OH group, the modification being selected from the group consisting of the 2′-OH group replaced by a H, alkoxy or OR, halogen, SH, SR, amino, or CN group, wherein R is a lower alkyl, alkenyl, alkynyl, or aryl.
7. The method of claim 6 , wherein the RNAi agent comprises a 2′-O-methyl oligonucleotide.
8. The method of claim 1 , wherein the RNAi agent contacts the organ via lipid-mediated delivery or as a component of a liposomal delivery preparation.
9. The method of claim 1 wherein the subject organ is from a mammal selected from the group consisting of human, pig, mouse, monkey, baboon, chimpanzee, and orangutan.
10. The method of claim 2 wherein the subject organ is from a mammal selected from the group consisting of human, pig, mouse, monkey, baboon, chimpanzee, and orangutan.
11. The method of claim 2 wherein the method further comprises alteration of mammalian stem cells.