Periodic Reporting for period 2 - TOLERANCE (Targeting innate immunity to induce TOLERANCE in transplantation)
Période du rapport: 2023-07-01 au 2024-12-31
TOLERANCE is a forward-thinking bioengineering program that pursues the bold ambition to develop and evaluate innovative nanomedicines for organ transplantation. Central to the TOLERANCE mission are (i) novel nanomedicine-based immunotherapeutics, (ii) targeting the immune system to induce tolerance, and (iii) creating a bridge between biomedical engineers at the Eindhoven University of Technology (TU/e) and clinicians/immunologists at the Radboud University Medical Center (Radboudumc). Since TOLERANCE’s start in 2022, we recruited and put together a team of talented PhD students and an assistant professor (Dr. Roy van der Meel) to work under the supervision of Prof. Dr. Willem Mulder. As per design, the different TOLERANCE investigators closely collaborate and work at both institutions. From their respective expertise, ranging from nanotechnology to nuclear medicine and in vivo imaging, the team members contribute to the TOLERANCE objectives. Through Mulder’s network in the USA and to efficiently kickstart the program, members have paid several visits to Mulder’s former Mount Sinai lab and his collaborators. These efforts resulted in the near completion of three extensive in vivo studies in a heart transplant mouse model. At the same time, in collaboration with RNA expert van der Meel, Mulder and the TOLERANCE team developed novel proprietary delivery technology. The delivery technology, referred to as the aNP platform, is inspired by the human body’s lipoprotein trafficking system. The first two papers about the aNP platform have been published, while several manuscripts are currently being prepared. Importantly, seven patent applications have been filed, which are being prosecuted by BioTrip, a biotech incubator that Mulder founded and in which TU/e, Radboudumc, biotech specialists work together to develop a trajectory for clinical translation. The work that Mulder, van der Meel and their team have done has not gone unnoticed. For example, Mulder and team members prominently featured in the BNNVARA documentary series “Leven naast de dood”, while van der Meel gave a TEDx talk. As per the TOLERANCE mission, its trainees are flourishing, as exemplified by their productivity and the dozen awards that they have won.
Transplantation is a life-saving procedure for patients who suffer from end-stage organ failure. Organ transplantation has been surgically feasible since the early 20th century, but it was the application of potent immunosuppression in the sixties and seventies that offered a solution to the previously insurmountable problem of organ rejection. Despite this major breakthrough, transplant recipients face substantial problems, including chronic rejection and severe adverse effects related to the chronic use of immunosuppressive drugs. These drugs suppress an already activated immune system. As T cells mediate organ rejection, it is considered a problem of adaptive immunity. However, innate immune responses precede T cell activation, TOLERANCE is a bioengineering effort to refocus organ transplant management to innate immunity. Since the start of the program, we have (i) untangled and published important innate immune mechanisms in organ transplantation, (ii) have developed innovative imaging methods to monitor immune responses longitudinally, (iii) have developed novel nanomedicines that target innate immunity and (iv) evaluated these nanomedicines in transplant mouse models, and (v) developed a new platform for RNA delivery to immune cells. Based on this work and the new technologies we devised, we are developing an intellectual property portfolio with the help of the biotech incubator BioTrip. Besides pursuing an alternative scientific vision organ transplantation, TOLERANCE is a training program for talented biomedical researchers and engineers. TOLERANCE trainees have presented their work at several international conference and have received multiple awards.
Using immune cells from volunteers and organ transplant patients, TOLERANCE has yielded unique insights in organ transplantation immune mechanisms. For example, we have mapped the role of a primitive, recently discovered immune memory known as trained immunity. In response to this finding, we developed a novel nanomedicine targeting trained immunity, which resulted in a spectacular prolongation of allograft survival in mice. Concurrently and in the same mouse model, we developed positron emission tomography imaging probes and methods to map trained immunity and T cell responses, non-invasively and longitudinally. Now we have identified new targets in organ transplantation, we will start applying our mRNA nanodelivery technology to therapeutically skew innate immune responses as a strategy to promote allograft acceptance. Given the translational character of the TOLERANCE program, we will continue our efforts to generate opportunities towards getting the new medicines closer to clinical application. These efforts include developing plans for chemistry manufacturing and controls (CMC) and scaling, IP protection and working with biotech professionals. Based on the TOLERANCE program, we are creating future career projects for existing trainees and new opportunities to continue this fascinating organ transplant program beyond the current ERC Advanced Grant.