This submission from the Childrens Hospital of UPMC and the University of Pittsburgh responds to the TriaNet RFA DK-13-010. This group of investigators, with extensive experience who are a current TrialNet center, has the resources, and ability to add to our current large number of affiliates and a track record demonstrating our ability to continue TrialNet participation as a center. In order to answer the objective of the RFA we have described in detail our record of recruitment into clinical trials of new onset patients an relatives at risk, with our success being based on our very large patient population and longevity of our research team. Increased support from the new Clinical Network Hub will support us in expansion of our efforts and especially our work with affiliates to increase their involvement and recruitment efforts. We are also able to include our fellow trainees in the TrialNet Investigations to train the T1D clinical trialists of the future. Our investigators and nurses have been very involved with all national TrialNet activities and committees and plan to continue or increase this involvement. In addition our center has proposed a randomized double blinded trial to evaluate the efficacy of a new FDA approved diabetes-suppressive cell vaccine, consisting of autologous monocyte- derived dendritic cells treated ex vivo with antisense phosphorothioate-modified oligonucleotides targeting the primary transcripts of the CD40, CD80 and CD86 co-stimulatory molecules (immunoregulatory)(iDC). The initial trial in patients with new onset Type 1 diabetes (T1D) has been approved in principal by the TrialNet steering committee pending funding. As in all the TrialNet interventions, the hypotheses to be tested in this study are that gene-engineered autologous iDC can attenuate or suppress the autoimmunity in: a) newly- diagnosed T1D, sparing residual beta cell mass, with restoration of insulin secretion as assessed by stimulated C- peptide levels. b) relatives with disease predicting islet autoantibodies, to sustain insulin secretion and to prevent or delay progression to clinical T1D. Currently, other than immune suppression with considerable potential side effects, there is no other means to reverse or prevent new-onset T1D. Our goal is to develop safe, easily administered interventions to suppress the autoimmune disease process. The strength of this proposal is the expertise and experience of the investigators, well established collaborations across centers and a novel intervention strategy.

Public Health Relevance

Research over the past decade has clearly demonstrated that the development of autoantibodies directed against the islet cells that make insulin are present for a few to many before the development of clinically overt type 1 diabetes mellitus. This collaborative research effort is the only very large well-oiled consortium that can test diabetes intervention strategies that might delay or prevent Type 1 Diabetes

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK061058-13
Application #
8776489
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M2))
Program Officer
Leschek, Ellen W
Project Start
2001-09-29
Project End
2019-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
$510,913
Indirect Cost
$179,151
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nathan, Brandon M; Boulware, David; Geyer, Susan et al. (2017) Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials. Diabetes Care 40:1494-1499
Bosi, Emanuele; Boulware, David C; Becker, Dorothy J et al. (2017) Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives. J Clin Endocrinol Metab 102:2881-2886
Hao, Wei; Wookwyk, Alyssa; Beam, Craig et al. (2017) Assessment of ? Cell Mass and Function by AIRmax and Intravenous Glucose in High-Risk Subjects for Type 1 Diabetes. J Clin Endocrinol Metab 102:4428-4434
Steck, Andrea K; Xu, Ping; Geyer, Susan et al. (2017) Can Non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes? J Clin Endocrinol Metab 102:2873-2880
Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group; Krischer, Jeffrey P; Schatz, Desmond A et al. (2017) Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial. JAMA 318:1891-1902
Yip, Linda; Fuhlbrigge, Rebecca; Atkinson, Mark A et al. (2017) Impact of blood collection and processing on peripheral blood gene expression profiling in type 1 diabetes. BMC Genomics 18:636
Ferrara, Christine T; Geyer, Susan M; Evans-Molina, Carmella et al. (2017) The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults. J Clin Endocrinol Metab 102:4596-4603
Ferrara, Christine Therese; Geyer, Susan Michelle; Liu, Yuk-Fun et al. (2017) Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development? Diabetes Care 40:698-701
Sosenko, Jay M (2016) Staging the progression to type 1 diabetes with prediagnostic markers. Curr Opin Endocrinol Diabetes Obes 23:297-305
Bundy, Brian N; Krischer, Jeffrey P; Type 1 Diabetes TrialNet Study Group (2016) A model-based approach to sample size estimation in recent onset type 1 diabetes. Diabetes Metab Res Rev 32:827-834

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