Abstract
Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX). An adenovirus (Ad) vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX) (Ad-E4-122aT-AHAFIX) maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.
Highlights
Hemophilia B is an X-linked blood coagulation disorder caused by deficiency or dysfunction of blood coagulation factor IX (FIX) due to genetic mutations in the FIX gene
Leaky Expression Levels of Ad Genes in the Neonatal Liver following Systemic Administration of Ad Vectors To determine whether Ad-E4-122aT suppressed the leaky expression of Ad genes in the neonatal liver, Ad gene expression levels in the liver were determined by real-time RT-PCR analysis following Ad vector administration
Leaky expression of the Ad genes occurred in the neonatal liver following administration of a conventional Ad vector, Ad-L2 (Figure 2B). mRNA levels of the Ad genes in the neonatal livers of Ad-L2-injected mice were about 3.4- to 14.2-fold lower than those in the adult livers of Ad-L2-injected mice (Figure 2B versus Figure S7)
Summary
Hemophilia B is an X-linked blood coagulation disorder caused by deficiency or dysfunction of blood coagulation factor IX (FIX) due to genetic mutations in the FIX gene. Patients with hemophilia B exhibit plasma FIX activity levels less than 40% of normal and are divided into three categories according to their plasma FIX activity levels: severe (
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