AAV gene therapy as a means to increase apolipoprotein (Apo) A‐I and high‐density lipoprotein‐cholesterol levels: correction of murine ApoA‐I deficiency

Vaessen, Stefan; Veldman, Robert Jan; Comijn, Elisabeth M.; Snapper, Jolanda; Sierts, Jeroen A.; Oever, Karin van den; Beattie, Stuart G.; Twisk, Jaap; Kuivenhoven, Jan Albert

doi:10.1002/jgm.1344

Cited by 15 publications

(12 citation statements)

References 48 publications

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“…HDL supplementation agents are also in clinical use, including infusion of synthetic or plasma-purified ApoAI and ApoAI mimetic peptides [13]. Gene addition has also been used to boost plasma ApoAI and HDL in preclinical studies using adenovirus and adeno-associated virus (AAV) vectors for delivery [14, 15]. …”

Section: Introductionmentioning

confidence: 99%

Targeted In Situ Gene Correction of DysfunctionalAPOEAlleles to Produce Atheroprotective Plasma ApoE3 Protein

Simons

Owen

2012

Cardiology Research and Practice

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Cardiovascular disease is the leading worldwide cause of death. Apolipoprotein E (ApoE) is a 34-kDa circulating glycoprotein, secreted by the liver and macrophages with pleiotropic antiatherogenic functions and hence a candidate to treat hypercholesterolaemia and atherosclerosis. Here, we describe atheroprotective properties of ApoE, though also potential proatherogenic actions, and the prevalence of dysfunctional isoforms, outline conventional gene transfer strategies, and then focus on gene correction therapeutics that can repair defective APOE alleles. In particular, we discuss the possibility and potential benefit of applying in combination two technical advances to repair aberrant APOE genes: (i) an engineered endonuclease to introduce a double-strand break (DSB) in exon 4, which contains the common, but dysfunctional, ε2 and ε4 alleles; (ii) an efficient and selectable template for homologous recombination (HR) repair, namely, an adeno-associated viral (AAV) vector, which harbours wild-type APOE sequence. This technology is applicable ex vivo, for example to target haematopoietic or induced pluripotent stem cells, and also for in vivo hepatic gene targeting. It is to be hoped that such emerging technology will eventually translate to patient therapy to reduce CVD risk.

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Section: Introductionmentioning

confidence: 99%

Targeted In Situ Gene Correction of DysfunctionalAPOEAlleles to Produce Atheroprotective Plasma ApoE3 Protein

Simons

Owen

2012

Cardiology Research and Practice

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“…APOA1 knockout mice lacking a functional APOA1 protein ( 12 ) were provided on a hyperlipidemic LDL receptor (LDLR) knockout background ( 13 ) by Dr. J. A. Kuivenhoven from the Amsterdam Medical Center (Amsterdam, The Netherlands).…”

Section: Animalsmentioning

confidence: 99%

HDL is redundant for adrenal steroidogenesis in LDLR knockout mice with a human-like lipoprotein profile

Hoekstra

Eck

2016

Journal of Lipid Research

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to adrenocortical cells under high steroidogenic pressure conditions, like stress. More specifi cally, probucol-induced lowering of both HDL-cholesterol and LDL-cholesterol levels in mice is associated with a >55% decrease in the glucocorticoid response to endotoxemia ( 1 ). Studies in LCAT and APOA1 knockout mice, respectively, have indicated that a specifi c decrease in plasma HDL-cholesterol levels is associated with a 25-50% decrease in the maximal adrenal glucocorticoid output ( 2, 3 ). Moreover, disruption of (adrenal-specifi c) HDL receptor function in mice is associated with a 40-50% decrease in the adrenocortical steroidogenic capacity ( 4, 5 ).Male carriers of functional mutations in the HDL biogenesis genes, ABCA1 and LCAT, display a decrease in the 24 h urinary excretion rate of adrenal-derived steroids ( 6 ). However, basal and stimulated plasma cortisol levels are similar in HDL-defi cient male ABCA1 and LCAT mutation carriers and their normolipidemic controls ( 6 ). Furthermore, both the urinary glucocorticoid excretion rate and cortisol response to corticotropin are unaltered in females with genetically low HDL ( 7 ). The presence of relatively low HDL-cholesterol levels is, thus, in striking contrast to what is observed in mice: not consistently associated with glucocorticoid insuffi ciency in humans.In vitro studies have suggested that both HDL and APOB-containing lipoproteins, i.e., VLDL and LDL, can theoretically supply cholesterol to adrenocortical cells ( 8-11 ). Importantly, human subjects exhibit a markedly different lipoprotein profi le as compared with mice. The majority of cholesterol in humans is carried by LDL, while the murine lipoprotein profi le is characterized by relatively low to absent levels of cholesterol associated with VLDL/LDL in the context of normal HDL-cholesterol levels. The relative importance of HDL-associated cholesterol as steroidogenic substrate can, thus, hypothetically be different between these two specifi c species due to the fact that human plasma, as compared with murine plasma, contains additional potential cholesterol sources, i.e., LDL Abstract The contribution of HDL to adrenal steroidogenesis appears to be different between mice and humans. In the current study, we tested the hypothesis that a difference in lipoprotein profi le may be the underlying cause. Hereto, we determined the impact of HDL defi ciency on the adrenal glucocorticoid output in genetically modifi ed mice with a human-like lipoprotein profi le. Genetic deletion of APOA1 in LDL receptor (LDLR) knockout mice was associated with HDL defi ciency and a parallel increase in the level of cholesterol associated with nonHDL fractions . Despite a compensatory increase in the adrenal relative mRNA expression levels of the cholesterol synthesis gene, HMG-CoA reductase, adrenals from APOA1/LDLR double knockout mice were severely depleted of neutral lipids, as compared with those of control LDLR knockout mice. However, basal corticosterone levels and the adrenal glucocorticoid response to stress we...

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“…Recently, Vaessen et al performed head-to-head comparisons of recombinant AAV-1, -2, -6 and -8 administered by different routes with the use of five different liver-specific promoters in addition to cytomegalovirus as single-stranded or as sc AAV vectors. They found that intravenous administration of scAAV8 results in the highest levels of human APOA1 expression in female Apoa1 -deficient mice (634 mg/dl), which persisted for the duration of the study (15 weeks) [85]. Cimmino and colleagues have extended upon these findings and have recently demonstrated stable long-term plasma levels of APOA1 in deficient mice after portal vein or muscle injection of AAV8.…”

Section: Disorders Associated Primarily With Altered Levels Of Hdl-cmentioning

confidence: 99%

Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies

Kassim

Wilson²,

Rader³

2010

Clinical Lipidology

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Despite numerous technological and pharmacological advances and more detailed knowledge of molecular etiologies, cardiovascular diseases remain the leading cause of morbidity and mortality worldwide claiming over 17 million lives a year. Abnormalities in the synthesis, processing and catabolism of lipoprotein particles can result in severe hypercholesterolemia, hypertriglyceridemia or low HDL-C. Although a plethora of antidyslipidemic pharmacological agents are available, these drugs are relatively ineffective in many patients with Mendelian lipid disorders, indicating the need for new and more effective interventions. In vivo somatic gene therapy is one such intervention. This article summarizes current strategies being pursued for the development of clinical gene therapy for dyslipidemias that cannot effectively be treated with existing drugs.

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AAV gene therapy as a means to increase apolipoprotein (Apo) A‐I and high‐density lipoprotein‐cholesterol levels: correction of murine ApoA‐I deficiency

Cited by 15 publications

References 48 publications

Targeted In Situ Gene Correction of DysfunctionalAPOEAlleles to Produce Atheroprotective Plasma ApoE3 Protein

Targeted In Situ Gene Correction of DysfunctionalAPOEAlleles to Produce Atheroprotective Plasma ApoE3 Protein

HDL is redundant for adrenal steroidogenesis in LDLR knockout mice with a human-like lipoprotein profile

Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies

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