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Principal Investigator: David H. Wagner
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $422,463
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract: Controlling the autoimmune inflammation in type 1 diabetes (T1D) has proven difficult.
Currently there are clinical trials to attempt controlling T1D that are having only marginal impact.
Desired primary outcomes include increasing of C-peptide, as a marker for beta cell restoration,
decrease insulin requirements, decreases in HbA1c, as a measure of systemic inflammation and
maintenance of peripheral blood lymphocyte counts. Current therapies have slowed C-peptide
loss marginally but not halted or reversed loss. None of the other primary goals have yet been
achieved in any of the current clinical trials. We created a novel approach to control pathogenesis
in T1D using a small peptide to modulate CD40 mediated inflammation. We completed pre-clinical
studies in mice that include toxicology/pharmacodynamic/pharmacokinetic studies on a peptide
that prevents diabetes onset in NOD mice and reverses hyperglycemia in 60% of diabetic NOD
mice. We have begun a veterinary clinical trial generating data that show, unlike current clinical
trial treatments, this approach increases C-peptide over time, reduces, by up to 90%, insulin
requirements, reduces glycated fructosamine, the veterinary equivalent of HbA1c, and does not
cause immune suppression or lymphocyte loss. We were granted a “Safe-to-Proceed” notice from
the FDA to begin Phase 1a/1b clinical trials in humans using this drug. This grant application is to
perform mechanism of action studies on this drug. We hypothesize that the drug, KGYY15
(OPT101 for FDA) binds to beta cell CD40 to prevent beta cell damage. We further hypothesize
that KGYY15 binds to peripheral blood T cells (TH40 cells specifically defined by us), B cells and
macrophages/dendritic cells to tolerize thus preventing further damage. We also will explore
developing this drug approach for islet transplants. Successful completion of this grant will provide
important information about how this drug works specifically during T1D.
Terms: <(TNF)-α><Adverse Experience><Adverse event><Antigen-Presenting Cells><Applications Grants><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B9 endocrine pancreas><Beta Cell><Binding><Blood Glucose><Blood Platelets><Blood Sugar><Bp50><Brittle Diabetes Mellitus><C-Peptide><CD154><CD40><CD40L><CD40LG><CDW40><Cachectin><Cachectin Receptors><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell surface><Cells><Cellular injury><Clinical><Clinical Treatment><Clinical Treatment Moab><Clinical Trials><Complete Blood Count><D-Isoglucosamine><Data><Dendritic Cells><Development><Diabetes Mellitus><Diabetic mouse><Dose><Drug Kinetics><Drug usage><Drugs><Effector Cell><Endocrine Pancreas><Family><Fructosamine><Future><Glycohemoglobin A><Glycosylated hemoglobin A><Goals><Grant><Grant Proposals><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Hemoglobin A(1)><Human><Humulin R><Hyperglycemia><IDDM><Immune><Immunes><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Inbred NOD Mice><Inflammasome><Inflammation><Inflammatory><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Intracellular Communication and Signaling><Invaded><Investigational New Drug Application><Islands of Langerhans><Islands of Langerhans Transplantation><Islands of Pancreas Transplantation><Islet Cell><Islets of Langerhans><Islets of Langerhans Grafting><Islets of Langerhans Transplantation><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Kidney Function Tests><Letters><Liver><Liver Function Tests><Lymphatic cell><Lymphocyte><Lymphocyte Count><Lymphocyte Number><Lymphocytic><MGC9013><Macrophage><Macrophage-Derived TNF><Maintenance><Marrow platelet><Measures><Mediating><Medication><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monoclonal Antibodies><Monocyte-Derived TNF><Murine><Mus><Mφ><NOD Mouse><Nesidioblasts><Non-Obese Diabetic Mice><Nonobese Diabetic Mouse><Novolin R><PK/PD><Pancreatic Islets><Pancreatic Islets Transplantation><Pars endocrina pancreatis><Pathogenesis><Pathogenicity><Pathway interactions><Peptide-based drug><Peptides><Peripheral Blood Lymphocyte><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase><Phase 1a/1b Clinical trial><Phase Ia/Ib Clinical Trial><Placebos><Platelets><Play><Production><Receptor Protein><Regular Insulin><Role><Safety><Series><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Sudden-Onset Diabetes Mellitus><T-Cell Activation><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><TNF><TNF A><TNF Alpha><TNF Receptor Family Protein><TNF Receptor Superfamily><TNF Receptors><TNF gene><TNF-α><TNFA><TNFR><TNFRSF5><TNFRSF5 gene><TNFSF5><TNFSF5 gene><TNFα><TRAP Gene><Thrombocytes><Time><Total Lymphocyte Count><Toxicology><Transplantation><Tumor Necrosis Factor><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Tumor Necrosis Factor-alpha><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Veiled Cells><Work><accessory cell><activate T cells><arm><autoimmune condition><autoimmune disorder><autoimmune inflammation><autoimmunity disease><autologous islet transplantation><biological signal transduction><cell damage><cell injury><cellular damage><connecting peptide><cytokine><damage to cells><design><designing><developmental><diabetes><diabetes control><diabetes mellitus control><diabetes mouse model><diabetic><drug action><drug use><drug/agent><first in man><first-in-human><glycation><glycemic control><hemoglobin A1c><hepatic body system><hepatic organ system><human study><human subject><hyperglycemic><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><injury to cells><innovate><innovation><innovative><insulin dependent diabetes><insulin dependent type 1><islet><islet auto transplantation><islet beta cell transplantation><islet cell transplant><islet cell transplantation><islet progenitor><islet transplantation><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><lymph cell><mAbs><member><monoclonal Abs><new approaches><non-enzymatic glycosylation><non-obese diabetic (NOD) mice><nonenzymatic glycosylation><nonobese diabetic (NOD) mice><novel approaches><novel strategies><novel strategy><p50><pathway><peptide drug><peripheral blood><pharmacokinetics and pharmacodynamics><pharmacologic><pre-clinical study><preclinical study><prevent><preventing><primary outcome><receptor><restoration><sham therapy><small molecule><social role><success><systemic inflammation><systemic inflammatory response><therapeutic peptide><therapeutic target><thymus derived lymphocyte><transplant><trial regimen><trial treatment><type I diabetes><type one diabetes><β-cell><β-cells><βCell>