Project Summary
Beginning in January 2012, the European Union has funded the European Clinical Study for the Application of Regenerative Heart Valves (www.ESPOIR-clinicaltrial.eu), coordinated by Hannover Medical School, Germany, with a grant of 5.2 Million Euros over a period of five years ending in December 2016. The core aim of ESPOIR was the implementation of a clinical study in regenerative medicine, which investigated the safety and efficacy of an innovative tissue-engineered human heart valve, which is tolerated by the patient’s immune system, has potential lifetime durability and even may grow with the patient.
The current gold standard for the treatment of certain heart conditions is the transplantation of mechanical or biological heart valves. However, both of these approaches also have significant disadvantages. Mechanical valves require lifetime coagulative treatment to thin the patient’s blood, which can be dangerous for children or pregnant women. For this reason, clinicians often prefer to use biological heart valves from humans or animals. However, these valves also degenerate within eight to ten years, rendering a further transplantation necessary. Each reoperation entails a higher risk for the patient and the mortality risk increases proportionally with the number of reoperations. To address this problem, the ESPOIR study has tested an innovative new approach using decellularized heart valves.
Decellularized heart valves are donated human heart valves (homografts), which undergo special decellularization treatment by Corlife oHG (www.corlife.eu), a small bio-tech enterprise, to remove all biological material from the homograft, leaving a collagen matrix. Before the start of the ESPOIR project, 45 children and young adults had already been treated with these valves in Chişinau (Moldova) and Hannover (Germany). While clinical follow-up was still in the early stages, none of these valves have needed to be explanted due to degeneration or rejection, and immunological follow-up revealed no abnormalities in these patients. Moreover, a functional development was observed in the diameter of the valves, which closely mimicked natural physiological growth.
The ESPOIR consortium brought together seven leading European clinics for paediatric cardiac surgery (London, Leiden, Padua, Zürich, Leuven, Chisinau and Hannover), four tissue banks (European Homograft Bank, Deutsche Gesellschaft für Gewebetransplantation, Fondazione Banca dei Tessuti di Treviso and Euro Heart Valve Bank), and an innovative bio-tech company, Corlife oHG. The heart valves for the study were procured by the tissue banks, sent to Corlife for decellularization, and subsequently transplanted at one of the clinical centres. Project management for the ESPOIR consortium was organized by the Leibniz University Hannover.
Project results
The initial phase of ESPOIR, which lasted almost three years, centred on obtaining approval for the decellularized heart valve and the setup of the study from the relevant regulatory authorities and European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). In this context, the ESPOIR study took on a pioneering role, as it was the first time that the authorities in all of the participating countries had been faced with the combination of regulatory approval for a decellularized human heart valve, cross-border movement of human tissue preparations, and the approval of a study testing such preparations. Heart valve decellularization can now be provided by Corlife oHG to any interested tissue bank or hospital fulfilling the European Directives on tissue donation. Reimbursement for this processing service already has been granted by health insurance systems in Germany, Austria, and Switzerland and is based on a uniform processing fee.
Following approval of the ESPOIR heart valve by the competent authorities during the second reporting period of the project, the individual clinical centers, in collaboration with Corlife and the tissue banks, were able to approach their local authorities and ethics councils to request the required approvals for clinical work. By the second half of 2015, all ESPOIR clinical centres had commenced with the clinical trial at their respective site. Since the inclusion of the first patient in August 2014, 121 patients in total have been treated with a decellularized pulmonary valve within the ESPOIR clinical trial.
The European Homograft Bank and Deutsche Gesellschaft für Gewebetransplantation, together with Fondazione Banca dei Tessuti di Treviso, Euro Heart Valve Bank and Corlife, have invested great effort in the establishment of a network of local tissue procurement organisations in addition to the ESPOIR consortium. This cooperation is important in order to increase donation, particularly from young donors. Work regarding the procurement of valves from post-mortem donors to further extend the donor pool has been performed during the third reporting period and is still in progress. Steps were taken in Hannover to create the appropriate infrastructure, including the audit of clinical rooms and specialized staff training.
Early in the project, the ESPOIR consortium implemented an advanced database infrastructure to secure long-term data acquisition on the overall performance of the transplanted heart valves. The ESPOIR Registry contains the data of all patients who received a decellularized homograft for pulmonary valve replacement and forms a solid basis for statistical analyses. At the end of the ESPOIR project 240 patients were documented within this registry with the aim of a ten-year follow-up for all patients.
First statistical analyses emerging from the project showed very promising results. The mortality rate for patients treated with decellularized pulmonary valves has been very low, overall 1.7%, with zero valve related mortality. Moreover, freedom from explantation has been excellent at 99 % since the first clinical implantation of the decellularised pulmonary valve more than ten years ago.
All project partners have been actively engaged in the communication and dissemination of the work and results of the ESPOIR project, both within the scientific community and general society at large, via press releases, presentations, publications and events. Ten peer-reviewed articles have already emerged from the project with several more in the pipeline. The ESPOIR website has been regularly updated (www.espoir-clinicaltrial.eu) with the latest information and news throughout the project and will be maintained after project end.
Building on the progress made in ESPOIR, a consortium led by ESPOIR’s coordinator, Prof. Haverich, was successful in obtaining further European funding for a “sister” project, focusing on aortic valve replacement using individualized regenerative allografts: the ARISE project (www.arise-clinicaltrial.eu).
Expected impact
The decellularization of human heart valves – or in the future possibly humanized animal valves - holds the potential to revolutionise the status quo in the clinical application of cardio-vascular tissue. If the early results based current data can be confirmed in the long-term, then the reduced immunogenic response in patients will lead to a corresponding reduction in re-operation rates and consequently will mean a decrease in mortality rates and improvements in the quality of life for patients with congenital heart defects. The extent of spontaneous recellularization, i.e. the population of the decellularized valve with the patient’s own cells, will determine the real long-term fate of the transplanted heart valve. In addition, a normal cell-type composition is necessary as basis for autologous regeneration of the transplanted collagen matrix. Conducting planned biopsies for the purposes of follow-up is not an option for ethical reasons and conclusions can be therefore only be derived in the rare cases of necessary other procedures or unplanned operations. The ESPOIR project members in the meantime have prepared a publication summarizing their current knowledge on spontaneous recellularization of decellularized human heart valves in vivo.
The ESPOIR project has proven to be groundbreaking in a number of aspects. The potential for lifelong durability of the valves tested within the ESPOIR project represents a fundamentally break with other currently available options for heart valve replacement: planned re-operations are regularly required for biological valve prostheses and mechanical prostheses significantly reduce the quality of life of the recipients. With decellularized heart valves, primary heart valve replacement during the initial repair of congenital heart defects may become feasible. If the long-term results are positive, current algorithms for heart valve replacement may have to be revisited. At present, valve replacement is delayed as long as possible to avoid more frequent re-operations.
Improvements in the decellularization technology also can be expected for the future, e.g. through application of growth factors facilitating recellularization by recipient`s own cells. Decellularized homograft valves also represent a good example for an evolving regenerative medicinal product which requires a standardized evaluation of quality, safety and efficacy. As there is limited experience in these procedures for new regenerative medical therapies or devices to date, it is important to provide models and pathways for this rapidly developing area of medicine. ESPOIR has made a significant contribution in this area in the implementation of a large-scale, European-wide, multi-centre trial, which can serve as a model for further cross-border trials in regenerative medicine.
Ethical issues in the evolving field of regenerative medicine are complex and of central importance. Within ESPOIR, these aspects were directly addressed via a dedicated Ethics and Governance Council. Clear and transparent information on ethics issues has been made available via the project website to minimize patient concerns and to raise awareness among the general public in Europe regarding the importance of tissue donation, in line with the aims of the EU Tissue Directive (2004/23/EC).
While the availability of donated human heart valves is main limitation of the current technique, a major breakthrough can be expected once humanized valves of animal origin are available for decellularization. In future scenarios such as these, Corlife will benefit from the experience garnered within the ESPOIR project in terms of communication with competent authorities for approval, large scale processing and quality assurance measures. Clinical implantation of such humanized tissue-engineered heart valves, e.g. originating from α–Gal knock-out animals, will need prior testing in clinical studies, which can also draw the ESPOIR model for clinical studies in regenerative medicine.