Approximately 400,000 people in the United States suffer from multiple sclerosis (MS), the most common cause of non-traumatic disability in young adults, and there is currently no cure. In MS patients, the myelin sheath that surrounds part of neurons in the central nervous system (CNS) is attacked by immune cells and eventually destroyed, leading to neurological degeneration. A treatment for MS that can help cells to regrow the myelin sheath is urgently needed and would have a profound impact on patients. Relevant to this need is the recent understanding that immune cells known as Regulatory T cells (Tregs) play a critical role in the repair process. In the CNS, Tregs can promote oligodendrocyte precursor cells (OPCs) to mature into oligodendrocytes, the cell type that is responsible for producing myelin in the CNS. A therapy that could be safely administered to patients to promote the expansion of Tregs and stimulate them to regenerate the myelin sheath through interactions with OPCs would be transformative in improving disease outcomes and quality of life for patients suffering from MS.

Focus Area: The focus of our project on promoting myelin repair addresses the FY20 MSRP Focus Area CNS Regenerative Potential in Demyelinating Conditions, as loss of myelin causes high levels of disability in MS patients. Our proposed technology is designed to increase the number of regenerative Tregs in the body, as well as to promote Treg interactions with OPCs that will lead to myelin production around neurons.

Scientific Objective/Rationale: We have designed synthetic, biodegradable microparticles, called Regenerative-Treg-Expanding Particles (RTEPs). RTEPs are decorated on their surface with a novel recombinant molecule that binds and activates Tregs in a targeted way, preventing side effects deriving from unwanted activation of other cell types. RTEPs are internally loaded with a second protein that causes Tregs to behave in a way that promotes tissue repair. We designed a plan to test our hypothesis that, following injection in mice, RTEPs will selectively stimulate growth of Tregs. We will use in vitro systems to confirm that the resulting Tregs promote myelin production by OPCs. Finally, we will implement mouse models that recapitulate MS-like symptoms of myelin loss, to achieve proof of principle that RTEPs treatment promotes re-myelination.

Impact on the Field: The RTEP technology that we are developing, used here for preclinical proof-of-concept studies in rodents, will be realized through the combined work of experts in biomaterials development, molecular engineering, immunology, and neurology. With the appreciation that complex interactions between cells of the immune system and oligodendrocytes and OPCs influence the processes of de- and re-myelination, our project (and its further development) is posed to contribute to a better understanding of these dynamics. Although multiple indirect demonstrations of the involvement of Treg in the re-myelination process exist, to our knowledge there is no understanding of how to contemporaneously promote the expansion of Treg that already exist in the body, and instruct them to act on the process of myelination. Proving that this in situ manipulation is indeed possible will prompt more in-depth investigations to define the key parameters to maximize beneficial outcomes. These studies will range from dissecting the molecular process of Treg differentiation, to elucidating the mechanisms of migration to the CNS, and to clarifying the molecular players implicated in the interaction with OPCs. The progress in our understanding of how to influence the course of MS promises to be vast.

From a therapeutic perspective, validating the potential of RTEP technology would represent a tremendous advance over attempts to adoptively transfer Tregs via the complex and extremely expensive processes of extraction from a patient, ex vivo expansion (with or without pharmacological or genetic manipulation), and reinfusion. Moreover, while the proposed work is based on mouse models, all of the proteins employed in RTEPs are human in origin. Using human proteins from the start will accelerate clinical translation of our technology. For the RTEP particle core, we use a biomaterial that is degradable and GRAS (generally regarded as safe), and this material has been used in several FDA-approved devices. The long clinical history of safety of this material will further shorten the developmental and regulatory paths of RTEPs. Thus, the studies proposed herein will be instrumental in mobilizing the rapid translation into the clinic.