000042385 001__ 42385 000042385 005__ 20240124114341.0 000042385 0247_ $$2doi$$a10.6083/bpxhc42385 000042385 037__ $$aETD 000042385 041__ $$aeng 000042385 245__ $$aA novel method of drug-mediated in vivo selective hepatocyte expansion for liver-directed gene and cell therapy 000042385 260__ $$bOregon Health and Science University 000042385 269__ $$a2023-12-15 000042385 336__ $$aDissertation 000042385 502__ $$bPh.D. 000042385 502__ $$gMolecular & Medical Genetics 000042385 520__ $$aLiver-directed gene and cell therapies represent a promising therapeutic strategy for many genetic disorders. However, they are hampered by inefficiency. The problem of inefficiency could be overcome by providing a selective growth advantage to corrected cells to allow them to repopulate the liver. This work aimed to characterize a novel method for in vivo selective expansion of hepatocytes using the common medication acetaminophen (APAP). In the liver, APAP is metabolized by cytochrome P450 enzymes to form a hepatotoxic intermediate. Cytochrome P450 enzymes require a cofactor, cytochrome P450 reductase (Cypor), for activity. Therefore, knockout of Cypor prevents APAP toxicity. A rare population of Cypor-deficient cells can thus be selectively expanded in vivo by APAP treatment. This work describes the application of this strategy to both liver-directed viral gene therapy and hepatocyte transplantation. 000042385 540__ $$fCC BY 000042385 542__ $$fIn copyright - single owner 000042385 650__ $$aGenetic Therapy$$028314 000042385 650__ $$aPhenylketonurias$$023968 000042385 650__ $$aAcetaminophen$$013294 000042385 650__ $$aGenetic Therapy$$028314 000042385 6531_ $$acell therapy 000042385 6531_ $$ahepatocyte transplantation 000042385 691__ $$aSchool of Medicine$$041369 000042385 692__ $$aDepartment of Molecular and Medical Genetics$$041428 000042385 7001_ $$aVonada, Anne$$uOregon Health and Science University$$041354$$10000-0003-0398-1898 000042385 8564_ $$951966fcc-ac42-493f-9128-9fc4e14d4376$$s28692971$$uhttps://digitalcollections.ohsu.edu/record/42385/files/Vonada.Anne.2023.pdf 000042385 909CO $$ooai:digitalcollections.ohsu.edu:42385$$pstudent-work 000042385 980__ $$aTheses and Dissertations 000042385 981__ $$aPublished$$b2023-12-18