Development of novel therapeutic options for diabetes mellitus type 1
Previous and Current Research
Islet transplantation has become a valuable therapy for patients with diabetes mellitus type 1. However, only selected patients with exhausted insulin therapy characterized by instable metabolic control and repeated severe hypoglycemia are transplant candidates. This strict indication is mainly due to the requirement for lifelong immunosuppression and the critical shortage for donor organs. Therefore, numerous research activities address these issues in order to provide beta cell replacement therapy to a broader cohort of patients with diabetes. The encapsulation of pancreatic islets within mainly alginate-based macro- or microcapsules with various physical configurations may allow protecting the islet graft without the need for immunosuppressive agents and moreover expanding the donor pool to animal tissue and novel insulin-producing cells. Despite major advances in encapsulation technology, a significant translation into clinical application is not evident. There are still issues that need to be resolved associated with graft oxygenation, immunprotection, inflammatory response, material biocompatibility, and transplantation site to list some of them. The recent advances in xenotransplantation and particularly in the field of stem cell-derived beta cells have generated a renewed scientific interest in encapsulation technology.
Our group is specifically working on improvement of islet isolation and transplantation protocols in clinical practice and the development of novel therapeutic options in the field of beta cell replacement with a clear translational “bench to bedside” approach by linking experimental research with preclinical and clinical work:
- Preclinical diabetes models and islet transplantation in small and large animals (including non-human-primates)
- Development of encapsulation technologies for immune-isolated islet transplantation (DFG BR 1179)
- Islet-xenotransplantation approaches (SFB/Transregio 127)
- Functional characterization and quality control of isolated human/porcine pancreatic islets
- Evaluation of alternative transplantation sites for islet transplantation
- Metabolic characterization of patients with diabetes mellitus type 1 following islet/pancreas transplantation
- Islet autotransplantation in patients following (sub-) total pancreatectomy
- Transplantation of macroencapsulated human islets in patients with brittle diabetes (collaboration with Kings college, London)
- Transplantation of macroencapsulated porcine islets in patients with brittle diabetes
Future Projects and Goals
- Optimization of current islet encapsulation technology (in cooperation with material scientists) for improved safety and efficacy
- Exploitation of alternative cell sources (xenogeneic primary islets, stem cell derived beta cells) for utilization in our encapsulation device (collaboration with Anthony Gavalas, CRTD)
- Preclinical evaluation of stem cell derived beta cells for diabetes treatment in preclinical models
Methodological and Technical Expertise
- Mouse, rat, porcine, and human islet isolation
- Experimental (small and large animal) islet transplantation
- Quality control assessment in cell culture and primary cells including functional assessments (oxygen consumption rate, perifusion assays, bioassays, etc.)
- General lab techniques (molecular biology, imaging, etc.)
Ludwig B, Reichel A, Kruppa A, Ludwig S, Steffen A, Weitz J, Bornstein SR
Islet transplantation at the Dresden diabetes center: five years’ experience.
Horm Metab Res. 47(1):4–8 (2015)
Ludwig B, Reichel A, Steffen A, Zimerman B, Schally AV, Block NL, Colton CK, Ludwig S, Kersting S, Bonifacio E, Solimena M, Gendler Z, Rotem A, Barkai U, Bornstein SR
Transplantation of human islets without immunosuppression.
Proc Natl Acad Sci U S A 110(47):19054–8 (2013)
Neufeld T*, Ludwig B*, Barkai U, Weir GC, Colton CK, Evron Y, Balyura M, Yavriyants K, Zimermann B, Azarov D, Maimon S, Shabtay N, Rozenshtein T, Lorber D, Steffen A, Willenz U, Bloch K, Vardi P, Taube R, de Vos P, Lewis EC, Bornstein SR, Rotem A.
The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs.
PLoS One 8(8):e70150 (2013)
Schubert U, Schmid J, Lehmann S, Zhang XY, Morawietz H, Block NL, Kanczkowski W, Schally AV, Bornstein SR, Ludwig B.
Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone.
Proc Natl Acad Sci U S A (2013)
Ludwig B, Ludwig S.
Transplantable bioartificial pancreas devices: current status and future prospects.
Langenbecks Arch Surg 400(5):531–40 (2015)
* shared first authorship