Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma.

Autor:	Kapelanski-Lamoureux A; Department of Anatomy and Cell Biology, McGill University, Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Chen Z; Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, La Jolla, CA 92037, USA., Gao ZH; Department of Pathology and Oncology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Deng R; Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, La Jolla, CA 92037, USA., Lazaris A; Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Lebeaupin C; Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA., Giles L; Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA., Malhotra J; Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA., Yong J; Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, La Jolla, CA 92037, USA., Zou C; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA., de Jong YP; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA., Metrakos P; Department of Surgery, McGill University; Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Herzog RW; Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA., Kaufman RJ; Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Electronic address: rkaufman@sbpdiscovery.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Dec 07; Vol. 30 (12), pp. 3542-3551. Date of Electronic Publication: 2022 Oct 14.
DOI:	10.1016/j.ymthe.2022.10.004
Abstrakt:	Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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