PhD Student The University of Hong Kong, Hong Kong
Abstract: Multiple Sclerosis (MS) is an unpredictable and chronic autoimmune disease that gravely affects the central nervous system (CNS). It is often characterised by neuroinflammation and demyelination of neurons. Currently, there is no cure for MS, and patients suffer from various degrees of physical incapacitation and cognitive impairment. Recent advancements in chimeric antigen receptor (CAR) technology and immunotherapy have provided an opportunity for engineering immune cells for MS treatment. This study will engineer lineage-negative hematopoietic stem and progenitor cells (Lin- HSPCs) with a CAR construct to generate CD19-targeting and TGF-β1 secreting CAR-microglia. The functions of the CAR construct will be validated in vitro using murine microglia, murine B-cell, and HEK-Blue TGF-β reporter cell lines. Subsequently, an experimental autoimmune encephalomyelitis (EAE) mice model induced by myelin oligodendrocyte glycoprotein (MOG) will be used to study the CAR-microglia’s effects in vivo. The MOG-induced EAE model is one of the most common mouse models for MS, and the MOG(1-125) peptide should be used for B-cell-dependent therapies. After myeloablative conditioning with Busulfan, injecting the engineered Lin- HSPCs into the CNS of EAE mice can allow cells to repopulate as microglia in the brain environment. The CAR-microglia will aim to phagocytose CD19+ autoreactive B-cells that play a pathogenic role in MS and simultaneously maintain an anti-inflammatory CNS environment. Since microglia are the resident macrophages of the CNS and may play a protective role in MS, equipping them with a CD19-derived single-chain variable fragment (scFv) and anti-inflammatory TGF-β1 payload will be a novel and beneficial therapy for MS. This method can be further adapted by modifying the antigen-binding domain and the payload of the CAR construct for different autoimmune and neurodegenerative diseases. This study hopes to contribute to the immunology and neuroscience fields by developing a tailorable and novel therapeutic approach using CAR-microglia.
