The development of fatal paralysis in amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the central nervous system (CNS). Inhibiting the persistent and toxic neuroinflammation and oxidative damage around motor neurons is a promising pharmacological strategy to prevent disease progression. Conventional anti-inflammatory drugs have limited CNS activity and have not been effective in ALS to date. Regulatory T cells (Tregs) are a subset of lymphocytes with inherent anti-inflammatory activity, are capable of penetration into the CNS, and higher numbers of Tregs are associated with slower disease progression in ALS patients. In this proposal, we aim to demonstrate that we can create a treatment that engages multiple mechanisms to treat ALS using gene-enhanced Tregs to deliver multiple therapeutic activities. We will use two classes of therapeutic genes that encode what we refer to as neurodegenerative disease modifying molecules (NDMMs). These genes provide enhanced therapeutic activity to Tregs, and this study is a way to demonstrate that gene-enhanced T cell therapy is a way to provide additional therapeutic activity in the CNS at the site of disease. We will test both secreted neuronal growth factors and proteins that prevent anti-oxidative damage. The objective of this proposed research is to test the hypothesize that NDMM-expressing Tregs will have enhanced therapeutic effects and prevent the death of neurons in ALS models. This proof-of-concept study will allow other NDMM-like molecules to be explored to modulate additional neuron survival or immunomodulatory pathways. A potential therapeutic breakthrough with therapeutic CAR Tregs would have a major impact on patients, their families, and clinical management of ALS.