Biomaterials-Enabled Delivery of Immunometabolic Modulators to Improve Treatment Options for Multiple Sclerosis in Veterans

点击翻译按钮获取中文摘要

Multiple sclerosis (MS) is an inflammatory, autoimmune disease resulting in motor deficits, pain, and cognitive deterioration. Studies investigating autoimmune disorders in military personnel have shown higher incidence of MS among Veterans, highlighting the importance of research in novel therapeutics for Veterans that are disproportionately impacted by the disease. Current MS drugs are non-curative and require life-long treatment to slow progression of disability. In addition, many treatment options are broadly immunosuppressive leaving patients susceptible to life-threatening infections. New strategies for MS treatment should increase efficacy, require fewer doses, and control specific aspects of pathological inflammation, leaving healthy immunity intact. MS occurs when lymphocytes (e.g., TH17 and TH1 T cells), attack myelin in the central nervous system that leads to neurodegeneration. Cell metabolism is emerging as a highly relevant therapeutic tool for interfering with activities of immune cell subsets. Of interest are intermediates of the tricarboxylic acid (TCA) cycle, demonstrated by the success of dimethyl fumarate ((DMF), Tecfidera) for treating relapsing-remitting MS. However, patients prescribed daily, oral DMF are at increased risk of immunosuppression that leads to potentially lethal complications from viral infection. Itaconate is derived from a TCA cycle intermediate and has been shown to suppress production of Interleukin-6 (IL-6), without impacting other cytokines, such as tumor necrosis factor a (TNFa), that play an important role in mounting immune responses. IL-6 secreted by dendritic cells (DCs) and macrophages promotes differentiation of inflammatory TH17 T cells at the expense of regulatory T cells (TREG) whose function is to suppress autoimmune activity. Preliminary studies indicate that itaconate protects mice from experimental autoimmune encephalomyelitis (EAE), the preclinical rodent model of MS. While promising, these effects required daily, high dose treatments. Biomaterials in the form of polymer particles offer features such as cell targeting and controlled release that improve treatment efficacy, specificity, and reduce the need for frequent dosing. Thus, the central hypothesis of this proposal is that particle-enabled uptake of itaconate by DCs and macrophages will reduce IL-6 production and shift the pathogenic inflammatory T cell response to a regulatory phenotype, providing protection against EAE. I will test this hypothesis through three specific aims: 1) design and validate particle synthesis and uptake; 2) determine the impact of itaconate packaged in polymer particles on immune cell metabolism and function; and 3) confirm and define the mechanisms of in vivo efficacy and specificity in EAE. Thus, VA support for this Career Development Award (CDA-2) will enable development of a novel strategy combining biomaterials with immunomodulatory metabolites that potentially offers more effective, specific treatments for Veterans with MS. This proposed research is part of a career and mentoring plan that will nucleate my development into a jointly appointed VA scientist and faculty member at an academic institution leading VA-funded projects. A mentoring team composed of VA researchers and clinician scientists with expertise in immune engineering, metabolism, and MS Veteran’s care will provide guidance in training areas to develop my conceptual and technical mastery of materials science, integration with the VA and its Veterans, and growth of my leadership skills. These goals are supported by my past training and productivity in studying immune-mediated diseases and will launch my entry into the VA conducting impactful research that tackles MS and autoimmune disorders affecting Veterans. Upon completion of this CDA-2, I will have 1) published high impact work facilitating my application for VA Merit and NIH R01 awards, and 2) established strong VA connections to nucleate complementary research directions. Together, this will prepare me to lead an independent, holistic research program built on the biomaterials-based delivery of metabolites that will benefit Veterans with autoimmune disorders such as MS.