Type 1 Diabetes (T1D) results from a breakdown of self-tolerance that is characterized by immune cell mediated destruction of the insulin-producing ?-cells in the pancreas. Ultimately, glucose metabolism is interrupted resulting in the development of life-threatening complications such as heart disease and renal failure. T1D affects an estimated 3 million Americans, with more than 30,000 new patients diagnosed annually, resulting in roughly $15B in health care costs in the US each year. It is thought that arrest of the autoimmune processes underlying this disease could avert the long-term complications associated with the disease and perhaps even reverse the disease process, given sufficient insulin-producing cells remain. Clinical intervention trials using immunomodulatory agents (e.g., anti-CD3) have failed to meet clinical endpoints, despite positive results in phase I/II trials, and traditional vaccine strategies providing auto-antigen or peptides alone failed to adequately block ongoing beta cell immunity. Thus, a new treatment strategy that is both potent and durable is required to effectively halt the ongoing attack in T1D. Regulatory T-cell (Treg)-based approaches are quickly gaining traction as a therapeutic strategy for treatment of auto-immune conditions. In this personalized therapeutic approach, endogenous populations of Tregs (widely considered the master regulators of the immune system) are expanded ex vivo, conditioned in factors to improve their tolerance-inducing capacity, and then re-introduced to the patient?s body. However, despite the promise exhibited by this approach to curb autoimmune diseases (including T1D) in animal models, the effects in humans are only transient due to rapid Treg death and loss of potency following adoptive transfer. Interleukin-2 (IL-2) is a cytokine known to be critical for Treg survival and function, but systemic introduction of IL-2 results in undesirable off-target effects. OneVax, LLC has pioneered a novel, biomaterial-based nanoparticle-Treg complex system for improved survivability and functionality of adoptively transferred Tregs. In this system, polymeric nanoparticles encapsulating IL-2 and harmine (a naturally occurring compound recently shown to induce ?-cells proliferation) are conjugated to Tregs, allowing for delivery of the encapsulated agents in a continuous and controlled manner. This approach has the potential to restore immune tolerance and ultimately restore glucose homeostasis. The objective of this phase I proposal is to conduct pre-clinical physiochemical and biological in vitro characterization of the nanoparticle-Treg conjugate therapy, and to determine its capacity to prevent diabetic onset in the therapeutically relevant non-obese diabetic mouse model. The preliminary data strongly suggests that this nanoparticle-Treg coupled therapy system holds promise for correcting autoimmune responses in T1D. Additionally, OneVax has established strategic collaborations with the Biomedical Engineering Department, College of Medicine and the Diabetes Institute at the University of Florida to boost OneVax?s capability to complete the desired goals.
Type 1 diabetes (T1D) is an autoimmune disease that carries a personal health burden that extends to a tremendous socioeconomic impact in the US, and cell based therapeutic approaches for T1D hold huge promise to correct these antigen-specific autoimmune responses. We seek to develop a potent and durable cell based therapy for T1D by conjugating polymeric nanoparticle encapsulating immunomodulatory agents to regulatory T-cells (Tregs). It is our belief that the infusion of these modified Tregs will combat the underlying autoimmune processes that drive T1D while also limiting off-target effects that result from systemic administration of immunosuppressive drugs.
