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Douglas McCarty, PhD

Award Name CCTS Pilot 2009
Award Date 04/01/2009

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Improving Islet Cell Transplants Through Gene Transfer

Douglas M. McCarty, PhD, Assistant Professor in the Department of Pediatrics, has been awarded one of nine pilot grants from the Pilot and Collaborative Translational and Clinical Science Program. These grants provide research teams with a one-year grant to create solutions to complex clinical and translational problems.

McCarty is using this grant to improve the treatment of Type 1 diabetes by refining the methods used to transplant pancreatic islet cells. Transplanted islet cells have low success rates because of immune and stress responses.

“By modifying the donor organ itself, so that the immune system can tolerate it better, we can avoid some of the immune suppressant treatments,” McCarty said.

This study will strive to increase the number of successful transplanted islet cells, which are currently limited by cell destruction.

McCarty and his team will refine the gene transfer technologies by using adeno-associated virus (AAV) vectors. McCarty has been working with AAV vectors for about 25 years and specifically as a gene transfer tool for the last 15.

McCarty and his collaborators first chose the best version of the virus to infect the islet cells. Two genes are then spliced into the virus and delivered into the pancreatic islet cells of donor mice. One of these genes, PD-L1 is suppresses the immune system that usually attacks insulin-producing cells. The other, is used for RNA interference targeted at ATF3. ATF3 triggers apoptotic pathways due to stress during transplants, resulting in cell death.

By transferring the islet cells into mice with a different tissue type, McCarty will be able to evaluate the therapeutic affects of this method. Usually the islet cells are rejected within two weeks, but if this treatment is successful it will delay that reaction.

As of now, islet cells are gathered from multiple donors, which limit the number of transplants that can be performed. Within the next year McCarty hopes to expand cell survival past the two-week mark, and use fewer islet cells that can survive longer. By using fewer islet cells, from one donor rather than two or three, it will be easier to match tissue types and alleviate stress responses in these cells. The research team will then focus on using this new technology in patients, exploring a portal vein transplant model which would release the treated islets into the liver.

McCarty hopes these techniques will improve islet cell survival rates, giving those affected with Type 1 diabetes better treatment options. This study also includes Dr. Tsonwin Hai, Department of Molecular and Cellular Biochemistry; Dr. Greg Hadley, Division of Transplantation; and Amer Rejab, Director of Pancreas and Islet Transplantation.

By Samantha Smith, Monday, October 12, 2009

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