Prednisolone Does Not Regulate Factor VIII Expression in Mice Receiving AAV5-hFVIII-SQ: Valoctocogene Roxaparvovec

• Published in: Molecular therapy. Methods & clinical development Vol. 17; pp. 13 - 20
• Main Authors: Zhang, Lening, Handyside, Britta, Murphy, Ryan, Sihn, Choong-Ryoul, Xie, Lin, Vitelli, Catherine, Harmon, Danielle, Sisó, Sílvia, Liu, Su, Bullens, Sherry, Bunting, Stuart, Fong, Sylvia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2020; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV; AAV5-hFVIII-SQ; ALT; AST; corticosteroids; FVIII expression; hemophilia A; prednisolone; Valoctocogene Roxaparvovec; hemophilia A; prednisolone; FVIII expression; AST; corticosteroids; AAV; ALT; Valoctocogene Roxaparvovec; AAV5-hFVIII-SQ
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2019.11.007

AAV5-hFVIII-SQ (valoctocogene roxaparvovec) is an adeno-associated virus (AAV)-mediated gene therapy vector containing a B-domain-deleted human factor VIII (hFVIII-SQ) transgene. In a phase 1/2 clinical study of AAV5-hFVIII-SQ for severe hemophilia A (FVIII < 1 IU/dL), participants received prednisolone to mitigate potential immune-mediated reactions to the gene therapy and demonstrated concomitant elevations in plasma FVIII levels, following a single administration of AAV5-hFVIII-SQ. To assess whether prednisolone is capable of directly modulating transgene expression or levels of circulating hepatic enzymes, C57BL/6 mice were given intravenous vehicle, 2 × 1013 vector genomes (vg)/kg AAV5-hFVIII-SQ, or 6 × 1013 vg/kg AAV5-hFVIII-SQ, followed by either daily oral prednisolone or water. Mice were euthanized 4 or 13 weeks after vector administration. Hepatic hFVIII-SQ DNA, RNA, and protein (immunostaining), plasma hFVIII-SQ protein and FVIII activity, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured. Liver hFVIII-SQ DNA, RNA, and plasma hFVIII-SQ protein and activity increased in a dose-dependent manner, with or without prednisolone. In summary, chronic prednisolone treatment in mice treated with AAV5-hFVIII-SQ did not modulate levels of liver hFVIII-SQ DNA, RNA, or the percentage and distribution of hFVIII-SQ-positive hepatocytes, nor did it regulate levels of plasma hFVIII-SQ protein or activity, or affect levels of plasma AST or ALT.