Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery of Sleeping Beauty Transposons: Implications for Non-Viral Gene Therapy of Systemic Disease

Human Gene Therapy
Elena L AronovichPerry B Hackett

Abstract

The non-viral, integrating Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic disease in mice, including hemophilia A and B caused by deficiency of blood clotting factors and mucopolysaccharidosis types I and VII caused by α-L-iduronidase (IDUA) and β-glucuronidase (GUSB) deficiency, respectively. Modified approaches of the hydrodynamics-based procedure to deliver transposons to the liver in dogs were recently reported. Using the transgenic canine reporter secreted alkaline phosphatase (cSEAP), transgenic protein in the plasma was demonstrated for up to 6 weeks post infusion. This study reports that immunosuppression of dogs with gadolinium chloride (GdCl3) prolonged the presence of cSEAP in the circulation up to 5.5 months after a single vector infusion. Transgene expression declined gradually but appeared to stabilize after about 2 months at approximately fourfold baseline level. Durability of transgenic protein expression in the plasma was inversely associated with transient increase of liver enzymes alanine transaminase and aspartate transaminase in response to the plasmid delivery procedure, which suggests a deleterious effect of hepatocellular toxicity on transgene expression. GdCl3 treatme...Continue Reading

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Citations

Nov 2, 2017·Bioscience Reports·Jaitip TipaneeMarinee K Chuah
Jun 23, 2019·Human Molecular Genetics·Priya S KishnaniDwight D Koeberl
Sep 19, 2017·Human Gene Therapy·Jaitip TipaneeMarinee K Chuah
Oct 3, 2018·Nature Reviews. Disease Primers·Frances M PlattCynthia J Tifft

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Methods Mentioned

BETA
transgenic
blood draws
ELISA
Assay
electron microscopy

Software Mentioned

GraphPad Prism
GraphPad
Photoshop

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