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.

中文翻译：

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泼尼松龙不能调节接受AAV5-hFVIII-SQ的小鼠的VIII因子表达：Valoctocogene Roxaparvovec。

AAV5-hFVIII-SQ（roxocalovovococcocogene roxaparvovec）是一种腺相关病毒（AAV）介导的基因治疗载体，包含B结构域缺失的人类因子VIII（hFVIII-SQ）转基因。在AAV5-hFVIII-SQ治疗严重血友病A（FVIII <1 IU / dL）的1/2期临床研究中，参与者接受了泼尼松龙以减轻对基因治疗的潜在免疫介导反应，并证明血浆FVIII水平随之升高，在单次施用AAV5-hFVIII-SQ之后。为了评估泼尼松龙是否能够直接调节转基因表达或循环肝酶水平，给C57BL / 6小鼠静脉注射溶媒，2×1013个载体基因组（vg）/ kg AAV5-hFVIII-SQ或6×1013 vg / kg AAV5-hFVIII-SQ，然后每日口服泼尼松龙或水。载体施用后4或13周使小鼠安乐死。测量了肝hFVIII-SQ DNA，RNA和蛋白质（免疫染色），血浆hFVIII-SQ蛋白质和FVIII活性，天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）。在有或没有泼尼松龙的情况下，肝hFVIII-SQ DNA，RNA和血浆hFVIII-SQ蛋白和活性均呈剂量依赖性增加。总之，用AAV5-hFVIII-SQ治疗的小鼠长期泼尼松龙治疗不能调节肝脏hFVIII-SQ DNA，RNA水平或hFVIII-SQ阳性肝细胞的百分比和分布，也不能调节血浆hFVIII- SQ蛋白或活性，或影响血浆AST或ALT的水平。和丙氨酸氨基转移酶（ALT）进行了测量。在有或没有泼尼松龙的情况下，肝hFVIII-SQ DNA，RNA和血浆hFVIII-SQ蛋白和活性均呈剂量依赖性增加。总之，用AAV5-hFVIII-SQ治疗的小鼠长期泼尼松龙治疗不能调节肝脏hFVIII-SQ DNA，RNA水平或hFVIII-SQ阳性肝细胞的百分比和分布，也不能调节血浆hFVIII- SQ蛋白或活性，或影响血浆AST或ALT的水平。和丙氨酸氨基转移酶（ALT）进行了测量。在有或没有泼尼松龙的情况下，肝hFVIII-SQ DNA，RNA和血浆hFVIII-SQ蛋白和活性均呈剂量依赖性增加。总之，用AAV5-hFVIII-SQ治疗的小鼠长期泼尼松龙治疗不能调节肝脏hFVIII-SQ DNA，RNA水平或hFVIII-SQ阳性肝细胞的百分比和分布，也不能调节血浆hFVIII- SQ蛋白或活性，或影响血浆AST或ALT的水平。