A chimeric-receptor T cell-based therapy for neurodegenerative disorders

Objects:
Alzheimer’s disease (AD) is a neurodegenerative disease and the primary cause of dementia. The robust synaptic and neuronal loss in the hippocampal and cortical areas of the brain is accompanied by the accumulation of misfolded proteins, such as the amyloid β (Aβ) peptide and neurofibrillary tangles, in affected sites in the parenchyma and vasculature of the brain. Together, these changes appear to be neurotoxic and cause a chronic innate neurotoxic inflammation. CD4 T cells play a key role in immune regulation and impact neuroinflammatory processes in the central nervous system (CNS), such as those observed in multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease. We recently showed that, intracerebroventricular (ICV)-injected Th1 T cells transducing to express brain-derived neurotrophic factor (BDNF), not only reduce innate inflammation and amyloid load, but also facilitate synaptic and neuronal protection.
Methods: We designed CD4 T cells expressing BDNF and CD4 T cells with chimeric receptors to target affected neurons in the brain and induce neuroregeneration. CD4 T cells carrying chimeric receptors are ICV-injected to the 5XFAD mouse model of AD and designed to migrate within the brain parenchyma and promote neuronal and synaptic repair.
Results: Our preliminary data show that CD4 T cells expressing chimeric receptors induce phosphorylation of key proteins in primary neurons which promote neuroprotection in culture. Furthermore, the ICV-injected CD4 T cells were able to upregulate synaptic proteins in the hippocampus of 5XFAD mice.
Conclusions
BDNF has been shown as a crucial component of neuronal repair in AD and other neurodegenerative disorders and we thus hypothesize that CD4 T cells targeted to neurons in the cortex and hippocampus will elicit a beneficial response. The chimeric receptors technology exhibits a novel cell-mediated signaling approach that may open a therapeutic platform for a variety of neurodegenerative, inflammatory and metabolic diseases.