Spatiotemporal tuning of myelin antigens and rapamycin for enhanced antigen-specific immune tolerance in multiple sclerosis.

Project Summary Multiple sclerosis (MS) is an autoimmune disorder thought to be caused by the self-attack on myelin sheath by autoreactive T cells. Despite improvements in technologies to temporarily suppress the immune system to mitigate the recurrence of MS attacks, there is no current solution that addresses the underlying autoimmune response in MS. For instance, existing injectable therapies such as beta-interferons are only temporary, lasting only about six months. While ocrelizumab is the first CD20 therapeutic antibody to show an effect in progressive MS, its clinical effects are rather modest, only showing a 6% reduction compared to placebo in both 12 and 24 week disability progression. Development of approaches that direct re-education of the immune system to be tolerogenic to self-antigens in MS is therefore an unmet need. In order to generate selective specific immune tolerance to myelin autoantigens, combinatorial delivery of antigen and immunosuppressive drugs (e.g. rapamycin) to antigen presenting cells is a powerful approach. However, dual delivery of antigen and rapamycin raises spatial and temporal considerations, as localization (space) and sequence (time) of antigen/rapamycin can dictate the magnitude of cis-priming of antigen presenting cells. To prime antigen presenting cells more efficiently by maneuvering the favorable spatiotemporal modality of rapamycin and antigen, we previously formulated a novel nanocarrier platform, Spatiotemporally Tuned Particle (STP), that delivers rapamycin and antigen specifically to antigen presenting cells in a preferred sequence. Our ability to tune the spatiotemporal delivery of antigen and rapamycin resulted in significant improvement of immune tolerance in mice, expanding Tregs and improving clinical symptoms in experimental autoimmune encephalomyelitis (EAE). In this program, we will utilize our promising platform to generate myelin autoantigen specific tolerance in EAE induced by multiple antigens found in the myelin sheath of spinal cord homogenate, which is representative of MS in humans. In aim 1, we fabricate and characterize STP candidates encapsulating myelin peptides and rapamycin. In aim 2, we validate the therapeutic efficacy of STP candidates in spinal cord homogenate EAE and investigate antigen- specificity and immune cell infiltration. Overall, our proposed approaches will ultimately allow researchers to leverage our platform for targeted and sequential delivery of multiple therapeutic agents to unlock their full potentials in MS and other autoimmune diseases.Project Narrative Multiple sclerosis (MS) is a serious autoimmune disorder, characterized by nerve damage occurring due to self-directed immune attack on the myelin sheath. To develop effective immune tolerance in MS, we leverage our previously developed nanoparticles that release antigen and immunosuppressant to target cells at the right time. By evaluating the pre-clinical efficacy of our nanoparticles in MS disease models that mimic human pathophysiology, this program promises the potential to enhance the needed efficacy of immunotherapy for MS and other autoimmune diseases.