Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis.
BACKGROUND
Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and adolescence. Mice with germ line interruptions in the Ldlr and Apobec1 genes (Ldlr(-/-)Apobec1(-/-)) simulate metabolic and clinical aspects of hoFH, including atherogenesis on a chow diet.


RESULTS
In this study, vectors based on adeno-associated virus 8 (AAV8) were used to deliver the gene for mouse Ldlr (mLDLR) to the livers of Ldlr(-/-)Apobec1(-/-) mice. A single intravenous injection of AAV8.mLDLR was found to significantly reduce plasma cholesterol and non-HDL cholesterol levels in chow-fed animals at doses as low as 3×10(9) genome copies/mouse. Whereas Ldlr(-/-)Apobec1(-/-) mice fed a western-type diet and injected with a control AAV8.null vector experienced a further 65% progression in atherosclerosis over 2 months compared with baseline mice, Ldlr(-/-)Apobec1(-/-) mice treated with AAV8.mLDLR realized an 87% regression of atherosclerotic lesions after 3 months compared to baseline mice. Immunohistochemical analyses revealed a substantial remodeling of atherosclerotic lesions.


CONCLUSIONS
Collectively, the results presented herein suggest that AAV8-based gene therapy for FH may be feasible and support further development of this approach. The pre-clinical data from these studies will enable for the effective translation of gene therapy into the clinic for treatment of FH.
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Sadik H
SH
Kassim
Hui
H
Li
Luk H
LH
Vandenberghe
Christian
C
Hinderer
Peter
P
Bell
Dawn
D
Marchadier
Aisha
A
Wilson
Debra
D
Cromley
Valeska
V
Redon
Hongwei
H
Yu
James M
JM
Wilson
Daniel J
DJ
Rader
D000818:Animals; D050197:Atherosclerosis / Q000628:therapy*; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000628:therapy*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000235:genetics
D017931:DNA Primers; D011973:Receptors, LDL