Type 1 diabetes (T1D) is a chronic disease caused by the autoimmune destruction of the insulin producing beta cells in the pancreas. Current treatment options for T1D are severely limited. All patients diagnosed with T1DM are placed on life-long insulin therapy and the current standard of care for adult patients with T1DM is intensive diabetes therapy to avoid long-term medical complications such as diabetic nephropathy, neuropathy, and retinopathy, among other complications (1, 2). T cells are believed to play a major role in the autoimmune destruction of pancreatic ? cells in T1D (3, 4). Many aspects of immune regulation including regulatory T cell (Treg) function has been found to be defective in T1D (4-10). Hence, restoration of Treg numbers and function to normalcy can be an effective strategy in preventing and/or treating T1D (11-14). Several TCR activation dependent methods have been developed for Treg expansion but they cannot be used in vivo, because such methods can activate Teff as well as Tregs, thus limiting the therapeutic efficacy. Methods for TCR-dependent ex vivo Treg expansion have been developed, but is impractical as the Tregs will have to be patient specific and requires repeated ex vivo expansion. Our recent studies have shown that soluble OX40L and Jagged-1 (Jag1) can cause a significant expansion of Tregs in vivo and suppress T1D in NOD mice. However, developing a clinically acceptable therapeutic consisting of two soluble ligands may face regulatory hurdles. We have developed mouse (m) and human (h) OX40L-Jag1- Fc fusion proteins that can be used to expand Tregs ex vivo. In our Phase-1 studies we will establish their therapeutic potential by testing their abilityto induce Tregs in vivo through the following aims: In aim-1, we will test if mOX40L-Jag1-Fc fusion protein can expand Tregs and delay/prevent the onset of hyperglycemia in NOD mice. In aim-2, we will test if hOX40L-Jag1-Fc is able to expand human Tregs in immunodeficient NSG mice reconstituted with human immune cells. Successful outcome of our studies would illustrate the potential clinical utility of our novel therapeutic. Subsequently, Absorption, Distribution, Metabolism, Excretion and Toxicity studies can be carried out to establish the safety of OX40L-Jag1-Fc required for IND filing to FDA. This novel therapeutic can be potentially used to effectively treat T1D and other autoimmune diseases with Treg insufficiency.
Public Health Relevance Statement: Public Health Relevance: Type 1 diabetes (T1D) is a chronic disease caused by the autoimmune destruction of the insulin producing beta cells in the pancreas resulting in severe hyperglycemia. Current treatment options for T1DM are severely limited. All patients diagnosed with T1D are placed on life-long insulin therapy and the adult patients are subjected additional therapy to avoid long-term medical complications such as diabetic nephropathy, neuropathy, and retinopathy. T cells play a major role in the autoimmune destruction of pancreatic ? cells in T1D. Many aspects of immune regulation, especially regulatory T cell (Treg) function, have been found to be defective in T1D. Hence, restoration of Treg numbers and function to normalcy can be an effective strategy in preventing and/or treating T1D. We have produced recombinant mouse (mOX40L-Jag1-Fc) and human (hOX40L-Jag1-Fc) chimeric proteins and successfully used them for the selective ex vivo expansion of mouse and human Tregs respectively. In the current proposal, we want to establish if treatment of NOD mice with the mOX40L-Jag1-Fc can cause Treg expansion and prevent/delay onset of T1D, and humanized NSG mice with hOX40L-Jag1-Fc can cause human Treg expansion. This novel therapeutic can be potentially used to effectively treat T1D, and other autoimmune diseases with Treg insufficiency.
Project Terms: absorption; Address; Adult; Affect; Asia; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; base; Beta Cell; Biological Availability; cell type; Cells; Chimeric Proteins; Chronic Disease; Clinical; Data; Data Reporting; Development; Diabetes Mellitus; diabetes mellitus therapy; diabetic; Diabetic Nephropathy; Diagnosis; effective therapy; Ensure; Europe; Excretory function; Extracellular Domain; Face; Family member; Future; Goals; Half-Life; Human; Hyperglycemia; IgG1; Immune; Immune system; in vivo; Inbred NOD Mice; innovation; Insulin; insulin dependent diabetes mellitus onset; Insulin-Dependent Diabetes Mellitus; jagged1 protein; Leukocytes; Life; Ligands; Mammalian Cell; Marketing; Medical; medical complication; Metabolism; Methods; Mus; Neuropathy; Normalcy; notch protein; novel therapeutics; Outcome; Pancreas; Patients; Phase; phase 1 study; Play; prevent; Production; Proteins; public health relevance; receptor; Recombinants; reconstitution; Regulation; Regulatory T-Lymphocyte; Renal clearance function; restoration; Retinal Diseases; Role; Safety; Serum; Signal Transduction; standard of care; T-Lymphocyte; TCR Activation; Testing; Therapeutic; Therapeutic Effect; therapeutic protein; TimeLine; TNF gene; TNFSF4 gene; Toxic effect; Treatment Efficacy
