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Ahram Jang,1 Boryana Petrova,1 Taek-Chin Cheong,1 Miriam E. Zawadzki,1,2,3 Jill K. Jones,1,3 Andrew J. Culhane,1 Frederick B. Shipley,1,4 Roberto Chiarle,1,5 Eric T. Wong,6 Naama Kanarek,1,2,4,* and Maria K. Lehtinen1,2,4,7,*
1Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, USA
2Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA
3Harvard, MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA
4Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA
5Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy
6Brain Tumor Center & Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
7Lead contact
*Correspondence
Abstract
For many cancer patients, chemotherapy produces untreatable life-long neurologic effects termed chemotherapy-related cognitive impairment (CRCI). We discovered that the chemotherapy methotrexate (MTX) adversely affects oxidative metabolism of non-cancerous choroid plexus (ChP) cells and the cerebrospinal fluid (CSF). We used a ChP-targeted adeno-associated viral (AAV) vector approach in mice to augment CSF levels of the secreted antioxidant SOD3. AAV-SOD3 gene therapy increased oxidative defense capacity of the CSF and prevented MTX-induced lipid peroxidation in the hippocampus. Furthermore, this gene therapy prevented anxiety and deficits in short-term learning and memory caused by MTX. MTX-induced oxidative damage to cultured human cortical neurons and analyses of CSF samples from MTX-treated lymphoma patients demonstrated that MTX diminishes antioxidant capacity of patient CSF. Collectively, our findings motivate the advancement of ChP- and CSF-targeted anti-oxidative prophylactic measures to relieve CRCI.
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