Enhanced persistence of CAR Tregs in the CNS for Alzheimer’s disease therapy

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with microglia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Data suggest that inflammatory microglia, the resident macrophages of the central nervous system, have a role in neurodegeneration and cognitive decline. Aberrant innate immune responses and altered inflammation are associated with AD and are involved in AD disease in murine models. Data show that inflammation modulators may be beneficial, but a challenge is how to delivery anti-inflammatory therapy that provides multiple mechanisms rather to the site of disease. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory activity. Tregs are found in the CNS under steady state conditions and increase in regions of CNS inflammation. Although the overall role for Tregs in AD is not well understood, many studies support a potential beneficial role for Tregs in AD. Our therapeutic strategy is to target Tregs to rebalance cerebral immunity, promote Aβ clearance, and limit neuron damage. However, key challenges for Treg therapy are that polyclonal Tregs do not target disease-associated antigens and there is no IL-2 in the CNS to support Treg persistence. We hypothesize that chimeric antigen receptor (CAR) Tregs targeted to AD-associated antigens that are engineered to persist will solve these key problems. We have chosen to use CARs that bind aggregated amyloid-beta (A-β), so that the CAR Tregs will be triggered at the site of A-β plaques. CAR cell therapy is a great approach for therapy because cells as drugs can traffic to sites of disease, persist in vivo (when engineered to do so), respond to the environmental cues (e.g. antigen) to trigger or limit activities, and delivery multiple therapeutic mechanisms.