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Benitec, Collaborators Report on Expressed RNAi Treatment for Heart Graft Rejection

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Researchers from the University of Western Ontario, in collaboration with Benitec Biopharma and stem cell firm Medistem, reported last month on the use of expressed RNAi technology to prolong the survival of an allogenic heart transplant by down-regulating certain genes involved in cell-mediated immunity.

The findings appeared in the American Journal of Transplantation.

“This is the first time that the innate immune system has been targeted for the purpose of transplantation tolerance,” Medistem CEO Thomas Ichim said in a statement. It also marks the second time Benitec and Medistem have published together, following the companies' January report on the use of expressed RNAi to inhibit IL-12 in order to treat autoimmune arthritis.

Benitec CEO Peter French added in the statement that the collaborative effort has been “fruitful” in demonstrating the potential of his company's RNAi approach in areas outside of its in-house focus.

Ichim told Gene Silencing News that the latest paper represents a sort of proof of concept to identify targets for therapeutic intervention and demonstrate that they can be silenced using an expressed RNAi approach.

Ultimately, the company aims to use its proprietary endometrial regenerative cells, which are essentially specialized mesenchymal cells, to develop stem cells that express these shRNAs, forming the basis for a transplant rejection treatment, he said.

“The beauty of [this approach] … is that the ERCs themselves have therapeutic activity,” which is expected to further enhance the RNAi effect, he added, citing a recent paper in the Journal of the American Medical Associationshowing that autologous mesenchymal stem cells could decrease the incidence of acute renal transplant rejections.

Ichim said that an investigational new drug application for such a therapy could be ready for submission to regulators within 18 months, although he noted that a phase I trial may be initiated by an academic investigator, rather than by Medistem directly. He also said that the company expects to acquire a license to Benitec's technology for the program.

According to the American Journal of Transplantation paper, heart transplantation is the only existing curative procedure for end-stage heart failure, but implanted grafts are routinely attacked by the host's adaptive immune system.

“Additionally, tissue damage resulting from organ procurement and ischemia/reperfusion damage leads to molecular signals that promote immunogenicity through the activation of dendritic cells,” which destroy the transplant, the study's authors wrote. “Other innate immune cells then infiltrate the graft, where they produce cytokines that inflict further injury and support the activity of alloreactive T cells.”

Immunosuppressive drugs can help prevent acute organ transplant rejection, but no effective approaches exist to address innate immune-mediated tissue injury and the subsequent graft dysfunction, they noted.

To address this issue, the research team, which also included investigators from Nanchang University and the Institute for Molecular Medicine, took aim at toll-like receptors, which activate innate immune responses, modulate adaptive immunity, and play a key role in transplant rejection.

“Upon sensing danger signals, such as injured tissues or extracellular matrix degradation components, TLRs activate various downstream signals that evoke inflammatory cytokines and chemokines, which mediate innate immune attack on grafts, and also modulate alloantigen-specific adaptive immune rejection,” they wrote.

Silencing common TLR adaptors, namely MyD88 and TRIF, using RNAi, therefore, “may provide a means to reduce TLR-mediated innate responses and indirectly attenuate cardiac graft rejection,” they noted.

The team first developed siRNAs against the two adaptors and tested them in vitro in dendritic cells. They found that the siRNAs not only silenced their targets but “significantly inhibited allogeneic T cell proliferation.”

They then used Benitec's expressed RNAi know-how to create DNA constructs encoding the myD88 and TRIF siRNAs, and treated mice then underwent heart transplants. Untreated mice survived five to eight days, while treated animals experienced “significantly prolonged cardiac allograft survival.” The addition of the immunosuppressive drug rapamycin to the RNAi treated further enhanced allograft survival.

“Tissue histopathology demonstrated an overall reduction in lymphocyte interstitium infiltration, vascular obstruction and hemorrhage in mice treated with MyD88 and TRIF siRNA vector plus rapamycin,” according to the American Journal of Transplantation paper. “Furthermore, treatment was associated with an increase in the numbers of [key] regulatory T cells and [T helper cell] deviation.”

Overall, the findings suggest that RNAi knockdown of MyD88 and TRIF genes impairs dendritic cell maturation, inhibits allogeneic T cell proliferation, and promotes the generation of Treg cells, which maintain peripheral tolerance while helping to suppress immune reactions and prevent autoimmune responses dangerous to the host, the paper's authors concluded.

“This study also provides proof-of-principle evidence that knocking down MyD88 and TRIF could be applied in combination with rapamycin to prevent graft rejection in heart transplantation,” they added.

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