A single infusion of valoctocogene roxaparvovec in adult patients with hemophilia A resulted in persistent expression of a modified human clotting factor VIII without long-term hepatic issues, according to study analyses published in Nature Medicine.

Histopathology of liver biopsy samples taken from 5 patients who had received infusions of valoctocogene roxaparvovec revealed no architectural distortion, dysplasia, fibrosis, or chronic inflammation. Furthermore, those hepatocytes which expressed the factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (hFVIII-SQ) protein showed no signs of endoplasmic reticulum stress. The patients had received their infusions between 2.6 and 4.1 years prior to the biopsy as part of a phase 1/2 clinical trial (NCT02576795).

Staining for vector genomes showed a trend for more cells transduced with higher vector doses with the participant receiving the lowest dose of 6 x 1012 vg/kg having very low levels of transduction (1.3%) while the patients receiving 4 x 1013 vg/kg (32.0% and 31.9%) and 6 x 1013 vg/kg (45.2% and 52.0%) having much higher levels.

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Expression levels of hFVIII-SQ RNA also showed transfusion dose-dependent trends, however, there was some variability between participants at the same doses. Participants 3 and 4 who received the highest dose had different levels of transduction as well as different levels of RNA expression. Participants 11 and 15 who received the middle dose both had similar transduction levels (32%) but had an almost 10-fold difference in RNA expression.

The researchers also discovered that the patients who had detectable levels of plasma FVIII displayed an inverse relationship between levels of RNA expression and FVIII levels. They suggested this difference may be due to variable levels of GRP78 RNA which affect the efficiency of folding and secretion of the hFVIII-SQ protein.

“This may imply inefficient protein translation, folding, posttranslational modification and/or secretion, and the endogenous capacity of cells to fold and secrete protein may be a factor,” the authors hypothesized about the variable expression levels.

“Overall, these results demonstrate persistent episomal vector structures following [adeno-associated virus serotype 5]-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.”

Valoctocogene roxaparvovec utilizes an adeno-associated virus serotype 5 vector to deliver the hFVIII-SQ gene. The hFVIII-SQ gene is a modified FVIII gene with the B-domain deleted and combined with a hybrid liver-selective promoter.


Fong S, Yates B, Sihn CR, et al. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat Med. 2022;28(4):789-797. doi:10.1038/s41591-022-01751-0