Community Research and Development Information Service - CORDIS

FP7

DIREKT Report Summary

Project ID: 602699
Funded under: FP7-HEALTH
Country: Sweden

Periodic Report Summary 2 - DIREKT (Disarming the intravascular innate immune response to improve treatment modalities for chronic kidney disease)

Project Context and Objectives:
Chronic kidney disease is world wide a major cause of end-stage renal disease (ESRD). 800,000 patients in Europe and in the US, respectively, require long-term treatment initially with peritoneal dialysis, followed by hemodialysis and kidney transplantation. Each ESRD patient on hemodialysis costs »€40,000 to €80,000 per year, has poor quality of life and an average life expectancy of only 4 years. Kidney transplantation totally changes life for an ESRD patient who can then return to normal
life, but this treatment is hampered by the low number of available kidney grafts. All these treatments are, however, associated with adverse reactions that cause damaging thromboinflammation, triggered by the intravascular innate immune system, which lead to poor results and non-function.
The overall aim of this project is to clarify the mechanisms and identify specific control points of regulation in these adverse reactions in order to be able to significantly improve the quality of hemodialysis devices and kidney grafts by applying new concepts of regulation in hemodialysis and kidney transplantation. We envisage that conveying a novel soluble complement inhibitor to the clinical stage via phase 1/2a clinical studies, creation of nano-profiled surfaces with low activating properties and generation of easy-to-apply one step-coatings for treatment of biomaterials (hemodialysis) and endothelial cell surfaces (kidney grafts) will significantly improve the treatment modalities of ESRD. The feasible hemodialysis treatment periods are anticipated to be extended, combined with an improved quality of life and in kidney transplantation attenuation of innate immune reactions will prolong the life expectancy of the graft and make more kidneys accessible for transplantation. All the novel techniques can be applied to other types of implantations, extracorporeal treatments and organ transplantations and in the future be used in xenotransplantation and stem cell therapies.
Project Results:
The work within DIREKT has proceeded according to the established plans with minor deviations. Ethics and regulatory affairs have been handled according to the timeline and tasks (WP1). DIREKTs inherent workflow scheme leads to an emphasis of work to certain WPs during different periods of the project. An intense interaction between partners has been developed that have resulted in a number of important collaborations and co-author publications. The focus of this second period of the project has been to further target regulation of vascular innate immunity by interventions in cross-talk between vascular and blood cells and on generation of nanoprofiled materials (WP2). Nanoprofiled surface have been shown to regulate both coagulation and complement activation on surfaces in contact with blood in vitro. Further progress has been made on the interaction between platelet, leukocytes and endothelial cells. The work on GPI and C3(H2O) as new ligands to CD11b/CD18 (Mac-1) and possible targets for therapeutic intervention have been finished (WP3). In addition, Del-5 has been shown to be an efficient inhibitor of the receptor in a transplantation setting (WP5). Great progress has also been reported for the development of thromboinflammatory regulators and for the conjugation to biosurfaces (cells and materials)(WP4/5). Mini Factor H is ready to be applied in experimental set ups and human recombinant CD39 is will be produced in larger quantities (WP3). Two major tracks of conjugation techniques for binding of regulators towards biomaterials and cells have been followed. The PEG-phospholipid has proved efficient for conjugation of regulators for cell and also to tissues and a multiarm PEG molecule (so-called Pluronic) has been shown to be similarly efficient for conjugation to material surfaces (WP4). Also the evaluation models using endothelial cells have been established within WP5. For instance, valuation of innate immunity inhibitors in whole blood models, in vivo models of transplantation and ischemia reperfusion injury are possible to perform. In WP6 both an ex vivo and an in vivo porcine model of allogeneic transplantation have been established. In the latter model, new and very encouraging results have been obtained with a PEG-phospholipid construct. Within WP5/6 new developed biomarkers of thromboinflammation (complement and coagulation) have been applied to samples from both humans and mice.
In WP2/WP7 experiments that will lead to a new nanostructured surface are well under way and with promising results. The effort to bring Compstatin from preclinical drug to clinical trials is progressing according to the time plan (WP8). Furthermore, Compstatin received orphan drug designation for the treatment of C3 glomerulopathy in early 2016 by the European Medicines Agency (EMA) and the U.S. Food Drug Administration (FDA).
Studies of the interaction between whole blood and regular dialysis membranes in order to gain understanding of the cross-talk between the intravascular innate immune system and whole-body inflammation in hemodialysis patients have been finished (WP9). A very appreciated face-to-face meeting within the Aegean conferences series was held in Rhodes, Greece, in the autumn of 2016 (WP10). The purpose was to disseminate information about the DIREKT activities and to encourage interactions related to end-stage renal disease (ESRD) between academic and industrial partners. In addition, dissemination of DIREKT activities to the
public, patients, industry, the research and medical community has been executed according to the intension of DIREKT, which includes a website (www.kidneydirekt.org) and also a project brochure published in issue 429 of the Parliament Magazine, 2016 (WP11). Furthermore, questions related to exploitation have been handled and support concerning patent protection by the establishment of an agreement of joint ownership. The Management Support Team (MST) has had regular project meetings every third month with the DIREKT partners during (WP12).
Potential Impact:
The focus of this project will be the chronic kidney disease known as end-stage renal disease (ESRD). Patients with this disorder will benefit greatly from the project, and so will patients
with other diseases such as cardiovascular disease (those receiving stents, cardiopulmonary bypass, heart transplantation) and liver disease (liver dialysis and transplantation), in which transplantation and extracorporeal treatment are important treatment modalities.
Development in DIREKT of active coatings and optimal nanostructured geometries to control
immune activation will be of great significance and make it possible to create 1) biomedical devices built of materials that meet the necessary requirements for stability, abrasion, and strength, and 2) applied coatings and nanostructured geometries that control aspects of intravascular innate immunity that are easy to apply to materials and cell surfaces.
In hemodialysis, the frequent treatments trigger side effects of whole-body inflammation, leading to a dramatically increased risk for cardiovascular disease. This thromboinflammation is the target of our work. Blockade of complement activation and other aspects of innate immunity will reduce inflammation in these patients and lower the risk of both arteriosclerosis and thrombosis.
Successful transplantation has an immense impact on the quality of life and normalizes the life and health of the patients, after periods of hemodialysis. The intravascular innate immune system is involved in various types of rejection during, immediately after, and in the long term after kidney transplantation. This rejection has severe consequences, such as limiting the selection of grafts for specific recipients and reducing the survival rate of the transplanted grafts. The actions planned within DIREKT will improve the quality of life for patients with ESRD by optimizing the conditions for kidney transplantation, with the aim of increasing the number of patients that can regain a normal life. In the future, techniques developed within this program will also be applicable to kidney xenotransplantation (and stem cell therapies), representing a large step forward, towards a greater availability of kidney grafts and transplant-related restoration of normal life for ESRD patients.
The phase 1/2a clinical trial of compstatin proposed will promote the development of this substance as an immunosuppressive drug for use in kidney transplantation. Transplantation as a therapeutic area is limited in terms of the expected number of treatments, making compstatin eligible for orphan designation and making further development of the drug more feasible. Our aim to develop an inhibitor for transplantation against the ABO barrier will be of great benefit for ESRD patients. It would facilitate an increase of the number of transplantations, since it leads to accommodation of the graft and thereby an increased accessibility of donor organs.
List of Websites:
www.kidneydirekt.org

Reported by

UPPSALA UNIVERSITET
Sweden

Subjects

Life Sciences
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