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. The immune system utilizes two important strategies to prevent the aberrant targeting and destruction of self-tissues: the production of regulatory T-cells (Tregs) and the limitation of inflammatory responses to prevent collateral damage. Recent studies have revealed that the intracellular protein suppressor of cytokine signaling-1 (SOCS-1) plays a crucial role in regulating immune responses and in the survival and phenotypic stability of regulatory T cells, and that defects in its production and availability plays a critical role in the manifestation of a variety of auto-immune diseases. Despite its obvious appeal as a potential therapy, enthusiasm has been dampened due to the extremely limited stability of therapeutically administered SOCS-1 in its pure form. We have managed to synthetically manufacture small peptide SOCS-1 mimetics that possess the functional capacity of SOCS-1, allowing for cost- and time-efficient production of this potential therapeutic. Furthermore, we have patented means of manufacturing injectable polymeric microparticles (MPs) encapsulating a variety of immunomodulatory agents allowing for sustained, tunable delivery of those agents to treat T1D. The objective of this Phase I proposal is to establish the feasibility of encapsulating our small peptide SOCS-1 mimetics in MPs, and to determine the efficacy of this MP system in the prevention of T1D onset in an animal model of the disease. The results from these studies will allow us to proceed to Phase II of the SBIR, in which studies will be conducted to satisfy the FDA requirements for the production of a clinical- grade drug suitable for Human Phase I/II clinical trials as a novel therapy for T1D. Our long-term goal is to develop an easily injectable therapy capable of prevention and reversal of a wide variety of auto-immune diseases, greatly enhancing the potential for widespread use. Our preliminary data strongly suggests that this therapy holds promise for correcting autoimmune responses in T1D. Additionally, our strategic collaborations with the Diabetes Center of Excellence at the University of Florida and the internationally recognized Sid Martin Biotechnology Institute bolster our ability 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 therapeutic approaches for T1D focusing on restoring immune tolerance mechanisms hold huge promise to correct the autoimmune response. We seek to combat the underlying autoimmune processes that drive T1D by utilizing a biomaterial-based delivery system to administer suppressor of cytokine signaling peptide mimetics designed to inhibit inflammatory cytokine responses and enhance regulatory T cell function, thereby restoring immune tolerance in a stable and robust manner.
