A transformative breakthrough has emerged from Sinai Health and the University of Toronto, as researchers unveil a pioneering technology that could potentially eliminate the need for immunosuppressive drugs in transplant patients. By genetically modifying donor cells, scientists have successfully created transplants that endured long-term in pre-clinical testing without the necessity for immune suppression.
In a groundbreaking study led by Andras Nagy, a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI) and professor in the University of Toronto’s Temerty Faculty of Medicine, the team achieved a significant milestone in addressing immune rejection—a major challenge in donor cell therapy.
“Transplant and cell therapy patients are required to take immunosuppressive drugs – sometimes for the rest of their lives to prevent their bodies from rejecting the transplant,” explained Nagy.
The study, published in the journal Nature Biomedical Engineering, instills hope for a revolutionary approach to transplantation. The genetically modified transplants, created through immune cloaking, could pave the way for an “off-the-shelf” supply of cells for therapies. According to Nagy, this could be safely administered to a broader spectrum of patients, making transplantation safer and more widely available.
“Our work paves the way for an ‘off-the-shelf’ supply of cells for therapies that could be safely given to many patients,” Nagy asserted.
The innovative strategy involves the genetic modification of donor cells, integrating a “kill-switch” technology called FailSafe with a method termed “immune cloaking.” By selecting eight key genes that regulate the immune system’s response to foreign cells, the researchers forced their overexpression in mouse embryonic stem cells. This prevented the immune system from recognizing the transplanted cells as foreign, effectively creating an immune cloak around the injected cells.
“Patient safety is paramount, and Dr. Andras Nagy is globally renowned for his sustained efforts to develop safeguards for future cell therapies,” said Anne-Claude Gingras, director of LTRI and vice president of research at Sinai Health.
Uncloaked cells typically face rejection within ten days of transplantation. In contrast, the cloaked cells persisted for more than nine months in pre-clinical testing—a remarkable achievement. “This is the first time that we’ve been able to achieve this length of time without rejection in a fully functional immune system,” Nagy emphasized.
Additionally, the researchers demonstrated that unmodified cells could escape rejection when embedded into the tissue created by the cloaked donor cells below the skin surface. This finding suggests that cloaked cells not only provide protection for themselves but also act as an immune-privileged implantation site for unmodified cells, opening possibilities for interspecies transplants.
Building on the success of mouse models, the researchers advanced to human application. By selecting human counterparts of the eight immunomodulatory genes, they created the first FailSafe and cloaked human cells. The co-culturing of these cells alongside human immune cells revealed their ability to escape destruction, showcasing the potential for human patients.
“This study gives invaluable insights into elegant alternatives to the toxic consequences of conventional immunosuppression,” said Michael Sefton, scientific director of Medicine by Design, a U of T institutional strategic initiative that primarily funded the research.
The research, still in its early stages, holds immense promise for regenerative medicine and cell-based therapies. Beyond transplantation, the breakthrough could significantly advance treatments for chronic diseases such as type 1 diabetes and heart failure, marking a pivotal moment in the evolution of medical science.
