Targeting Proinflammatory Molecules Using a Chimeric Receptor to Reduce Inflammation and Tauopathy

Brain inflammation has recently been shown to exacerbate Alzheimer’s disease pathologies, and our goal is to suppress inflammation by developing a chimeric receptor that degrades proinflammatory molecules, combined with gene therapy for a long-term treatment approach.

Brain inflammation has recently been shown to progress Alzheimer’s disease pathologies. Our studies aim to develop therapeutic strategies that suppress inflammatory molecules regulating brain inflammation. We further aim to combine these strategies with gene therapy that will provide brain specificity and a long-term treatment approach.

We developed a novel lysosomal degrading chimeric receptor (LDCR) that targets extracellular proteins for lysosomal degradation. This innovative approach offers a strategy for breaking down proinflammatory molecules. Using AAV-based gene therapy to express LDCR specifically in the brain will provide a platform to reduce neuroinflammation by degrading proinflammatory molecules in Alzheimer’s disease (AD), while avoiding the potential adverse effects of suppressing peripheral inflammation and weakening the immune system. The ability to reduce brain inflammation without affecting the immune system is especially important for older AD patients, who may already have a compromised immune system.

Emerging evidence suggests brain inflammation contributes to the progression of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Therefore, our strategy that aims at suppressing brain inflammation may have therapeutic value for several neurodegenerative diseases. In addition, our chimeric receptor approach is amenable to targeting autoantibodies that play a pivotal role in the development of autoimmune diseases. Autoimmune diseases are a diverse group of chronic conditions characterized by the production of aberrant autoantibodies that target cellular antigens in tissues, including the brain.