title: Adeno-associated virus serotype 8 gene therapy leads to significant lowering of plasma cholesterol levels in humanized mouse models of homozygous and heterozygous familial hypercholesterolemia.
abstract: Familial hypercholesterolemia (FH) is a life-threatening genetic disease caused by mutations in the gene encoding low-density lipoprotein receptor (LDLR). As a bridge to clinical trials, we generated a "humanized" mouse model lacking LDLR and apolipoprotein B (ApoB) mRNA editing catalytic polypeptide-1 (APOBEC-1) expression and expressing a human ApoB100 transgene in order to permit more authentic simulation of in vivo interactions between the clinical transgene product, human LDLR (hLDLR), and its endogenous ligand, human ApoB100. On a chow diet, the humanized LDLR-deficient mice have substantial hypercholesterolemia and a lipoprotein phenotype more closely resembling human homozygous FH (hoFH) than in previous mouse models of FH. On injection of an adeno-associated virus serotype 8 (AAV8) vector encoding the human LDLR cDNA, significant correction of hypercholesterolemia was realized at doses as low as 1.5 × 10(11) genome copies (GC)/kg. Given that some patients with heterozygous FH (heFH) cannot be adequately treated with current therapy, we then extended our studies to similarly "humanized" mice that were heterozygous for LDLR deficiency, and that have a lipoprotein phenotype resembling heterozygous FH. Injection of AAV8-hLDLR brought about significant reduction in total and LDL cholesterol at doses as low as 5 × 10(11) GC/kg. Collectively, these data demonstrate the safety and efficacy of the liver-specific AAV8-hLDLR vector in the treatment of humanized mice modeling both hoFH and heFH.
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-3403, USA.
authors.forename: Sadik H
authors.initials: SH
authors.lastname: Kassim
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Suryanarayan
authors.initials: S
authors.lastname: Somanathan
authors.forename: William
authors.initials: W
authors.lastname: Lagor
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobs
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Billheimer
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D002784:Cholesterol / Q000097:blood; D003564:Cytidine Deaminase / Q000172:deficiency; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000628:therapy*; D015151:Immunoblotting; D007371:Interferon-gamma; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*
chemical_list: D011973:Receptors, LDL; D007371:Interferon-gamma; D002784:Cholesterol; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase