I am involved in a variety of different translational and clinical research projects, most related to pediatric diabetes. Some of the recent and on-going projects are described below:
1. Prevention of type 1 diabetes: I am actively involved in a series of clinical trials with immuno-modulatory agents to alter the natural course of type 1 diabetes. Since 2002, I have served as the Clinical Center director for the NIH sponsored program TrialNet, a multi-center research consortium that develops trials to delay or prevent the onset of type 1 diabetes in those at risk, or prolong endogenous insulin secretion (the honeymoon phase) in those with new onset disease. UCSF is one of 18 international centers for this study. I have an active role in the consortium, in development and institution of various network studies, and membership on several key committees (including service as chairman on the Ancillary Studies Committee for 9 years, and now chair of Clinical Monitoring). Funding began in 2002, and we have successfully re-competed for funding until 2014.
In addition, I have served as the site director for a novel study evaluating the role of an anti-CD3 monoclonal antibody in preserving endogenous insulin-producing beta cells (the honeymoon phase) in those with new onset type 1 diabetes. The initial phase 1 / 2 study results were published in the N Engl J Med 2002, and this has been followed by our 2 year and 5 year follow-up data (Diabetes 2005, Clinical Immunology 2009). These exciting results were confirmed in an independent study with a related drug in Europe, and have spawned a series of further NIH sponsored studies to build on these initial findings. One study is to determine if repeated courses of the antibody, rather than a single course, improve on long term efficacy. We are also evaluating the window of opportunity for anti-CD3 therapy, with a trial to evaluate subjects further from the time of initial diagnosis. We have also recently launched an anti-CD3 prevention trial for subjects found to be at high risk for type 1 diabetes (based on genetic, immunologic, and metabolic screening). As a further extension of these efforts, I have developed a trial to use a polyclonal rather than monoclonal antibody approach against T cells. To that end, I am the study principal investigator for an NIH sponsored multi-center new onset type 1 diabetes trial with anti-thymocyte globulin, with the primary outcome to be reached in June, 2012. We have also just launched a trial with anti-thymocyte globulin coupled with granulocyte colony stimulating factor, which may be synergistic. I am also principal investigator on multi-center trial with Imatinib in new onset diabetes that is under development.
We are now moving beyond immunosuppressive regimens and moving on to cell based therapies for type 1 diabetes. I am a co-principal investigator of a phase 1 to evaluate the safety and efficacy of autologous regulatory T cells in subjects with recent onset type 1 diabetes. I am also co-investigator on a recently funded grant from the California Institute for Regenerative Medicine to develop beta cell replacement therapy from stem cells. These latter two projects are in collaboration with Jeffrey Bluestone, UCSF Diabetes Center, and others.
2. Other diabetes interests: I am also involved in other clinical research efforts in Pediatric Diabetes, including a) efforts to improve outcomes in Latinos with diabetes; b) transition from pediatric to adult diabetes care; c) use of pumps and continuous glucose sensors; d) optimizing in-patient diabetes care; e) exome sequencing to characterize novel defects causing diabetes and related disorders.
3. Disorders in water balance: An additional area of investigation is characterization of the nephrogenic syndrome of inappropriate antidiuresis. I was the senior author on a study published in the N Engl J Med 2005 first describing this novel disorder in water balance, resembling Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), but secondary to an activating mutation in the vasopressin type 2 receptor. We are now pursuing further aspects of this condition, including the frequency; optimal means of therapy, including novel receptor agonists and antagonists; and the effects of such mutations in vitro. I am also involved in planning a clinical trial in pediatrics with an arginine vasopressin antagonist, termed an aquaretic, which has only been used in adults to date.