Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis in Hyperlipidemic Rabbits

Wacker, Bradley K.; Dronadula, Nagadhara; Bi, Lianxiang; Stamatikos, Alexis; Dichek, David A.

doi:10.1161/atvbaha.117.309565

Cited by 35 publications

(31 citation statements)

References 94 publications

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“…53 So far, several interventional approaches targeting apoA-I have been developed 54, 55 and a few of them revealed beneficial effects against atherosclerosis in humans, 56 but none of these strategies have resulted in clinical use. A recent manuscript published in ATVB demonstrated that apoA-I vascular gene therapy targeting endothelial cells shows a protective effect against atherosclerosis in hyperlipidemic rabbits, 57 suggesting that increased apoA-I expression in the endothelium is atheroprotective. In addition, apoA-I mimetic peptides have been continuously developed in parallel with the investigation of its functionality in vivo .…”

Section: High-density Lipoproteinmentioning

confidence: 99%

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

Matsuura

Kanter

Bornfeldt

2019

ATVB

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Section: High-density Lipoproteinmentioning

confidence: 99%

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

Matsuura

Kanter

Bornfeldt

2019

ATVB

View full text Add to dashboard Cite

“…Another approach to gene therapy may be that of transducing arterial endothelial cells with the helper dependent adenoviral (HdAd) vector expressing apoA-I [93]. High fat fed rabbits underwent bilateral carotid artery gene transfer, one artery receiving a control vector (Hd Null) and the other receiving an apoA-I expressing vector.…”

Section: Hdl Therapythe Coronary Atheroma Target (Figure 1)mentioning

confidence: 99%

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

et al. 2019

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Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health. KEY MESSAGES High-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries). Knowledge on the activity of high-density lipoproteins on health have however significantly widened. HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.

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“…Sustained expression of endothelial cells has been demonstrated upon intra-arterial delivery of HC-AdVs. Using this approach, significant improvement has been observed in high fat diet-fed rabbits [137]. Co-expression of Apo AI and the ATP-binding cassette subfamily A, member 1 (ABCA1) is feasible using HC-AdVs, and this combination can improve the cholesterol efflux from endothelial cells [138].…”

Section: Liver-directed Gene Supplementationmentioning

confidence: 99%

High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy

Ricobaraza

González-Aparicio

Mora-Jimenez

et al. 2020

IJMS

101

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The adaptation of adenoviruses as gene delivery tools has resulted in the development of high-capacity adenoviral vectors (HC-AdVs), also known, helper-dependent or “gutless”. Compared with earlier generations (E1/E3-deleted vectors), HC-AdVs retain relevant features such as genetic stability, remarkable efficacy of in vivo transduction, and production at high titers. More importantly, the lack of viral coding sequences in the genomes of HC-AdVs extends the cloning capacity up to 37 Kb, and allows long-term episomal persistence of transgenes in non-dividing cells. These properties open a wide repertoire of therapeutic opportunities in the fields of gene supplementation and gene correction, which have been explored at the preclinical level over the past two decades. During this time, production methods have been optimized to obtain the yield, purity, and reliability required for clinical implementation. Better understanding of inflammatory responses and the implementation of methods to control them have increased the safety of these vectors. We will review the most significant achievements that are turning an interesting research tool into a sound vector platform, which could contribute to overcome current limitations in the gene therapy field.

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Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis in Hyperlipidemic Rabbits

Abstract: In rabbits with severe hyperlipidemia, transduction of vascular endothelial cells with an apo A-I-expressing HDAd yields at least 24 weeks of local apo A-I expression that durably reduces atherosclerotic lesion growth and intimal inflammation.

Cited by 35 publications

References 94 publications

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy

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