Impact

1. Specific scientific and technical impact

1.1 Diabetes mellitus

Evaluation of beta-cell mass in the course of diabetes and monitoring new therapeutic strategies:
A reliable method for (repeated) non-invasive quantification of beta-cell mass in vivo in humans will enhance our understanding of the pathophysiology of both type 1 and type 2 diabetes. Progressive beta-cell loss is characteristic for T1D, but the natural history of beta-cell loss remains to be determined. Beta-cell dysfunction is a hallmark of type 2 diabetes, but it is not known at what stage of the disease this occurs. Individual patients show large differences regarding the relative contribution of insulin resistance or insulin deficiency to the diabetic state. Also the deterioration of beta-cell function varies. Development of diabetes is thought to occur in steps. At early stages, beta-cell mass may even be increased. Development of beta-cell mass and beta-cell function in the course of disease do not necessarily show a direct correlation, i.e. in particular stages of the disease, the beta-cell function may be impaired while the beta-cell mass is not significantly reduced or vice versa. If BetaImage succeeds in developing a technique for non-invasive quantification of beta-cell mass, it will be possible for the first time to follow the natural history of the decline of functional and afunctional beta-cell mass in both T1D and T2D. A method to non-invasively measure beta-cell mass in vivo in humans would also enable us to study the effects of different diabetes treatments on beta-cell mass which may result in a more individually-tailored therapy, based on the principle underlying defect. Such a technique would for example enable us to monitor beta-cell mass in vivo in patients receiving anti-diabetic medication thought to increase beta-cell mass in T2D.
Quantification of beta-cell mass could also be used for monitoring in patients with type 1 diabetes undergoing islet transplantation which is a promising method for restoration of glucose homeostasis. To obtain a sufficient number of functioning islets, islets are typically isolated from two cadaveric donor pancreata and transplanted. As yet, it is unknown how many of these islets will contribute to glucose homeostasis directly after transplantation, i.e. how many islets survive during the first weeks after transplantation. Using a number of approximately 800,000 - 900,000 islets per patient, the rate of insulin-independent patients is approximately 80% after one year, which drops to about 65% after two years. Monitoring of the beta-cell mass after transplantation may help to optimize immunosuppressive therapy regimens and thus help to increase the rate of insulin-independent ß-cell recipients. PET-tracers targeting would enable us to follow beta-cell mass after transplantation without requiring potentially toxic pre-transplantation labelling of beta-cells.
Diabetes research:
In diabetes research, a non-invasive method for quantification of beta-cell mass (including beta-cell loss and beta-cell neogenesis) would help to perform longitudinal studies in animal models addressing the questions related to beta-cell mass mentioned above. The methods developed in BetaImage would allow researchers to image beta-cell mass in vivo by small animal PET and SPECT technique but also to follow individual islets or subgroups of islets in vivo with xf-FDOCT. This would greatly improve monitoring of new therapies in animal models, speed up their translation into phase 1 clinical trials, and would help to reduce the number of animals required because longitudinal studies would no longer require immunohistochemical determination of beta-cell mass in pancreatic specimen from killed animals. Furthermore, the effects of new drugs on individual islets (with respect to blood-flow, islets biodistribution of beta-cell markers etc.) could be monitored. Nanoparticles targeting beta-cell specific proteins or other structures on beta-cells or endothelium surface would enable MRI-based detection and follow-up of beta-cells, allowing both metabolic and anatomical imaging of islets.  

1.2 Tracer development

The successful setting up of a new streamlined methodology for efficient tracer development based on combination of a functional genomics/Systems Biology approach and optimal in vitro and in vivo models for rapid evaluation of tracer micro-distribution in vivo will help to increase efficacy of tracer development. In this way, high-throughput tracer screening will become possible in a multidisciplinary approach. Furthermore, evaluation of tracer micro-distribution might increase our knowledge about tracer behaviour allowing to develop new strategies for tracer-based imaging. Imaging techniques and technology developed within BetaImage will have a translational characteristic. The technological advance of BetaImage will therefore foster research in other areas such as cancer research or receptor targeted therapies with radioactive tracers.

2. Expected return to the European industry and economy

BetaImage is at the interface between biology, medicine and technology, and brings together academic experts in these fields. It is expected that several of the deliverables of the project such as:

• newly identified beta-cell targets, development of new ligands,
• development of new cell and animal models of diabetes,
• development of novel diagnostic tracers,
• testing of ligands with potential therapeutic benefits,
• development of innovative imaging methods,
• development of new radioactive and multimodal tracers,
• refinement in real-time and high resolution imaging, etc.

could be of interest for a number of European industries, working in both closely related and unrelated fields. In view of the large, and rapidly expanding economy of the diabetes field, it is anticipated that any deliverable which could offer a significant value even to only a small fraction of the diabetic patients, would represent a worth investment for further development. This is true not only health wise but also from an economic standpoint. Therefore such deliverables will be of interest to small- and large-scale pharmaceutical companies, as well as for companies active in medical imaging. It has been noted in the previous sections that the search for new ligands targeted to beta cells may serendipitously lead to the identification of ligands for other cell types, most likely with tumoral and/or neuronal characteristics. Once validated, the interest for marketing of these products will largely exceed the diabetes area and, by sparing the enormous costs of chronic, life-threatening diseases, be of considerable economical interest to the European Union. We therefore vision the milestones of our project as important stimuli for European industry and economy.