Intranasal Delivery of TGFα – A Novel Therapeutic Approach for Lesion Resolution in Multiple Sclerosis? (P7-3.001)

Abstract

<h3>Objective:</h3> We here evaluate the therapeutic potential of tissue-protective TGFα for the resolution of CNS inflammation. <h3>Background:</h3> After acute lesions in the central nervous system (CNS) such as in Multiple Sclerosis (MS), the interaction of microglia, astrocytes and infiltrating immune cells defines the inflammatory microenvironment in the CNS which can either induce resolution of inflammation or lead to its chronification. However, the interaction between microglia, astrocytes and infiltrating immune cells and their respective contribution to the resolution of tissue damage is poorly characterized. In this context, we have recently identified microglia-derived TGFα as a novel driver of recovery in MS and its preclinical animal model experimental autoimmune encephalomyelitis (EAE). Here, we describe its regulation over the course of the disease and investigate its translational potential during acute inflammation in the CNS. <h3>Design/Methods:</h3> We here use CRISPR–Cas9-based genetic perturbation models, high-dimensional flow cytometry, immunohistochemistry and magnetic resonance imaging (MRI), as well as fine-tuned <i>in vitro</i> assays to investigate cellular targets, net effects and therapeutic potential of microglia-derived TGFα for recovery in MS and its preclinical animal model experimental autoimmune encephalomyelitis (EAE). <h3>Results:</h3> During acute CNS inflammation, microglia secrete TGFα in a highly regulated temporospatial manner. We show that microglial TGFα is required for EAE recovery by decreasing the number of infiltrating T cells and pro-inflammatory myeloid cells, as well as reducing oligodendrocyte loss, axonal damage, and demyelination. In a therapeutic approach, intranasally delivered TGFα diminishes the pro-inflammatory profile of astrocytes and CNS infiltrating immune cells, while promoting neuronal survival and lesion resolution, therefore promoting clinical recovery. <h3>Conclusions:</h3> Together, we show that TGFα acts on glial and infiltrating cells to promote the resolution of CNS inflammation. TGFα signaling might represent a novel checkpoint of CNS recovery, which offers therapeutic potential to promote recovery in acute and chronic stages of MS. <b>Disclosure:</b> Mrs. Loesslein has nothing to disclose. Mr. Linnerbauer has nothing to disclose. Dr. Tsaktanis has nothing to disclose. Dr. Quintana has nothing to disclose. Prof. Rothhammer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Rothhammer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Prof. Rothhammer has received research support from German Research Foundation. The institution of Prof. Rothhammer has received research support from European Research Council.