Abstract 1509: Discovery of choroid plexus targeted gene therapy to protect cancer chemotherapy-related cognitive impairment

Abstract Chemotherapy-induced neurotoxicity in non-cancerous cells can cause lifelong complications including cognitive impairment, also known as chemobrain, which is a devastating side effect for cancer patients and survivors. One mechanism by which chemotherapy damages healthy cells is through oxidative stress. The choroid plexus (ChP)-cerebrospinal fluid (CSF) system delivers important health-promoting factors, such as the antioxidant superoxide dismutase 3 (SOD3), to increase survival in response to oxidative stress, while cell-intrinsic pathways protect neurons from oxidative damage. However, the consequences of chemotherapy on ChP and CSF composition are unknown. Here, we show that the chemotherapeutic drug methotrexate (MTX) induces a global metabolic change in the brain, which is reflected in the CSF. Leveraging metabolomics, we found that MTX caused oxidative stress in the CSF of MTX-treated mice, including a reduction in important antioxidant metabolites. The ChP is the main source of secreted SOD3 in the brain. Following MTX treatment in mice, ChP-SOD3 expression was diminished as well as CSF-SOD3 was decreased. Moreover, overall CSF-antioxidant activity was compromised, indicating that cancer chemotherapy damaged the ChP, resulting in an impoverished CSF with reduced antioxidant capability. MTX-induced oxidative stress may also be tracked to tissues in contact with CSF that are functionally vulnerable to the toxicity of cancer chemotherapy. For example, glutathione peroxidase (GPx) enzyme activity was decreased in the hippocampus, where lipid peroxidation was elevated following MTX treatment. Analyses of CSF samples from primary and secondary central nervous system (CNS) lymphoma patients supported our hypothesis that MTX treatment is associated with diminished antioxidant levels in patient CSF. We employed an intraventricular adeno-associated viral (AAV) gene delivery technique to augment SOD3 production by the ChP. ChP-SOD3 gene therapy inhibited oxidative stress indicators in CSF and mitigated MTX-induced toxicity in the adjacent hippocampus. Furthermore, this gene therapy prevented MTX-induced anxiety as well as short-term learning and memory deficits. Collectively, our findings on AAV-based gene therapy via the ChP-CSF system may represent an underutilized approach for widespread and long-term delivery of health-promoting factors to the brain. Citation Format: Ahram Jang, Boryana Petrova, Taek-Chin Cheong, Miriam E. Zawadzki, Jill K. Jones, Andrew J. Culhane, Frederick B. Shipley, Roberto Chiarle, Eric T. Wong, Naama Kanarek, Maria K. Lehtinen. Discovery of choroid plexus targeted gene therapy to protect cancer chemotherapy-related cognitive impairment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1509.