The Future of Cell Transplantation

Abstract

Strategies aimed at restoring beta cell mass generally fall under either Replacement (islet transplantation and stem cell differentiation), Reprogramming (from non-insulin-producing cells) or Regeneration (replication and induction from endogenous precursors/stem cells). Objectives of cellular therapies and regenerative medicine strategies for treatment of DM are to reverse the disease condition and prevent the development of the severe chronic complications that can affect most organ systems in a large proportion of patients over time. A multicenter Phase III trial of transplantation of adult pancreatic islet has been recently completed and is moving towards a Biological License Application (BLA) in the USA, while novel strategies to engineer an intra-abdominal mini-endocrine pancreas are currently tested in pilot clinical trials. In T1DM, the additional challenge of the underlying autoimmune condition imposes consideration of strategies that would restore self-tolerance or abrogate the effects of autoimmunity, so that the immune system can no longer destroy the new insulin producing cells introduced either by regenerating, reprogramming or replacement (e.g., transplantation of pancreatic islets or stem cell derived insulin producing cells). Abrogation of autoimmunity or its effects could be achieved by either tolerance induction strategies or immune protection (e.g., engineered microenvironment or selective permeability physical barriers like those introduced by micro-, conformal- or nano-encapsulation). Any therapeutic strategy, to be considered must avoid side effects such as those associated with life-long immunosuppression, which now limits the indications of adult islet transplantation to the most severe cases of T1DM. There is a broad consensus on the idea that stem cells will eventually replace adult pancreatic islets in the future. However, the jury is still out regarding the candidate cell type/s and approach that will ultimately succeed. Current differentiation methods for adult stem cells span from signal-driven approaches, to genetic manipulation and even strategies of in-vivo maturation after systemic administration. The more suitable alternatives between replacement, reprogramming and regeneration strategies should be further developed in preclinical model systems and tested in pilot clinical trials, while carefully assessing safety, efficacy, cost-effectiveness and the relative potential for scale up, to offer a realistic therapeutic option for most patients affected by diabetes. LECTURER'S PROFILE Dr. Ricordi is Department of Surgery and Director of the University of Miami's Diabetes Research Institute and Cell Transplant Program (www.diabetesresearch. org). His current research interests include cellular therapies, immune tolerance induction, stem cells and regenerative medicine for the treatment of diabetes. He spearheaded The Cure Alliance and the Diabetes Research Institute Federation to eliminate geographic barriers to collaboration. He has served as President of the Cell Transplant Society, the International Pancreas and Islet Transplant Association, and served on the council of the American Society of Transplant Surgeons and The Transplantation Society. He currently serves as founding president of The Cure Alliance (www.thecurealliance.org). Dr. Ricordi has authored over 700 scientific publications, and as an inventor, he has been awarded 24 patents.