Type 1 diabetes mellitus is an autoimmune disease whose etiopathogenesis lies in the selective destruction of the insulin-producing beta cells of the islets of Langerhans in the pancreas. The current insulin replacement therapy strategies are not fully effective at recapitulating tight glucose control. While transplantation of intact islets of Langerhans offers the potential to restore physiologic glycemic control, the requirement for life-long immunosuppressive interventions carries with it significant risks of rendering the islet transplants dysfunctional. However, these strategies can lead to an array of other problems including kidney failure and a risk of malignancy. The objective of this collaborative application combining the efforts of the Diabetic Clinic of the Children's Hospital of Pittsburgh, The Diabetes Institute and the Cancer Institute of the University of Pittsburgh is to extend and adapt our initial successful dendritic cell-based approach of prolonging the onset time of diabetes in the NOD mouse. We will inject new-onset diabetic NOD mice with gene engineered DC to manipulate the immune system with the objective of preserving residual beta cell mass that can sustain reduced glycemia or even a return to normoglycemia. Once we confirm this, we propose to initiate a safety trial in new-onset diabetic human volunteers. In this approach, volunteers will be given a single injection of gene-engineered DC and safety will be assessed by different and complementary criteria. The gene-engineered DC will consist of autologous DC propagated ex vivo from peripheral blood mononuclear cells and treated with short, double-stranded oligodeoxyribonucleotide decoys for the transcription factor NF-kB (NF-kB ODN). In a similar approach, antisense oligonucleotides targeted to the CD40, CD80 and CD86 primary transcripts will be used in place of the NF-kB decoys. We divide this application into two sections. The first will deal with studies primarily in the NOD mouse to demonstrate proof-of-principle and will culminate in a application for a limited safety trial in human diabetic volunteers. The second will extend the safety trial into a larger population of diabetics and will culminate in a preliminary examination of the potential of our approach to preserve residual beta cell mass and function as assessed by stimulated C-peptide level and hemoglobin Ale as a surrogate marker. If the results are encouraging, these approaches could be attempted in a larger human population with an objective of lowered insulin requirements, decreased dosage and perhaps a gradual tapering off of insulin. The ultimate result could include less intensive or even a complete cessation of insulin replacement therapy in newly-diagnosed diabetics as well as, perhaps, a means of preventing diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33DK063499-04
Application #
7119507
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Akolkar, Beena
Project Start
2002-09-30
Project End
2010-01-31
Budget Start
2006-08-01
Budget End
2010-01-31
Support Year
4
Fiscal Year
2006
Total Cost
$546,841
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
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