Bile-duct proliferation as an unexpected side-effect after AAV2-LDLR gene transfer to rabbit liver.

Abstract:

:Familial hypercholesterolemia (FH) is an inherited disease of lipoprotein metabolism caused by a defect in the LDL receptor (LDLR) leading to severe hypercholesterolemia, and associated with an increased risk of coronary heart disease and myocardial infarction. We have developed a gene therapy protocol for FH using AAV2, AAV9 and lentiviral vectors and tested safety and efficacy in LDL receptor deficient Watanabe Heritable Hyperlipidemic rabbits. We show that LV-LDLR produced a significant long-lasting decrease in total serum cholesterol whereas AAV9-LDLR resulted only in a transient decrease and AAV2-LDLR failed to reduce serum cholesterol levels. A significant pathological side effect, bile-duct proliferation, was seen in the liver of AAV2-LDLR rabbits associated with an increased expression of Cyr61 matricellular protein. Special attention should be given to liver changes in gene therapy applications when genes affecting cholesterol and lipoprotein metabolism are used for therapy.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Hytönen E,Laurema A,Kankkonen H,Miyanohara A,Kärjä V,Hujo M,Laham-Karam N,Ylä-Herttuala S

doi

10.1038/s41598-019-43459-1

subject

Has Abstract

pub_date

2019-05-06 00:00:00

pages

6934

issue

1

issn

2045-2322

pii

10.1038/s41598-019-43459-1

journal_volume

9

pub_type

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