Brian Lawson, PhD | The Scintillon Research Institute
Competition Sponsor: National Academy of Medicine
Awardee Year: 2025
Multiple sclerosis (MS) is a debilitating autoimmune disease in which T and B lymphocytes infiltrate the central nervous system (CNS), attacking myelin sheaths and leading to progressive neurological decline. The disease becomes more prevalent and severe with age. While current therapies moderate relapses, they often suppress the peripheral immune system and do not selectively target pathogenic cells within the CNS. In this project, we propose a very novel, localized immunotherapy strategy that utilizes the resident immune cells of the CNS—microglia (MG)—to achieve targeted immune modulation without systemic toxicity. We will employ advanced chimeric antigen receptor (CAR) designs to engineer MG (CAR-MG) that specifically recognize and eliminate autoreactive T and B cells in the CNS. Additionally, we will develop “armored” variants that secrete neurotrophic and myelin repair factors to promote functional recovery. First, we will design a panel of CAR-MG constructs targeting pan-T/B cells and specific T-cell subsets, such as Th17 cells. These constructs will incorporate MG-specific promoters, safety switches, and inducible gene expression systems. Second, we will evaluate the therapeutic efficacy of CAR-MG in the well-established experimental autoimmune encephalomyelitis (EAE) mouse model of MS, assessing neuroinflammation, demyelination, and functional recovery. We will also confirm that CAR-MG can be rapidly ablated if necessary. This research can address critical gaps in MS treatment by confining CAR-based immunotherapy to the CNS and providing MG with neuroprotective capabilities. If successful, our platform will promote long-term immune tolerance in the CNS, preserve peripheral immunity, and enhance myelin repair, potentially revolutionizing MS care.