Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial

Nicholls, Stephen J.; Puri, Rishi; Ballantyne, Christie M.; Jukema, J. Wouter; Kastelein, John J.P.; Köenig, Wolfgang; Wright, R. Scott; Kallend, David; Wijngaard, Peter; Borgman, Marilyn; Wolski, Kathy; Nissen, Steven E.

doi:10.1001/jamacardio.2018.2112

Cited by 148 publications

(96 citation statements)

References 34 publications

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“…Future research on HDL-based therapeutic approaches for AD will benefit from the considerable safety and efficacy data gathered from clinical trials using HDL formulations, including recombinant apoA-I proteins, apoA-I mimetics, and plasma-derived apoA-I, all of which were developed to treat atherosclerosis [62,63]. CER-001 and MDCO-216 are recombinant proteins of the wildtype and Milano sequences of apoA-I, respectively, which were both well tolerated as infusions in phase II clinical trials but were unsuccessful in meeting the primary endpoint of reduced atherosclerosis [64][65][66]. ApoA-I mimetic peptides, such as D-4F and L-4F, were developed to overcome the production difficulties associated with full-length recombinant proteins and improve oral bioavailability.…”

Section: Discussionmentioning

confidence: 99%

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

et al. 2019

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Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice . Methods APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice. Electronic supplementary material The online version of this article (10.1186/s13195-019-0497-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

et al. 2019

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“…Administration of MDCO-216 (ApoA-1 Milano/POPC) promoted ABCA1-mediated cholesterol efflux and pre-β HDLs in healthy volunteers and patients with stable coronary artery disease [60,61]. Subsequently, HDL mimetic containing the recombinant apoAI Milano (five weekly infusion of MDCO-216) was developed to determine its effect on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial [62]. However, administration of MDCO-216 failed to promote the regression of the atherosclerotic plaque when combined with statin therapy [62].…”

Section: Mdco-216mentioning

confidence: 99%

“…Subsequently, HDL mimetic containing the recombinant apoAI Milano (five weekly infusion of MDCO-216) was developed to determine its effect on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial [62]. However, administration of MDCO-216 failed to promote the regression of the atherosclerotic plaque when combined with statin therapy [62].…”

Section: Mdco-216mentioning

confidence: 99%

Roles of Reconstituted High-Density Lipoprotein Nanoparticles in Cardiovascular Disease: A New Paradigm for Drug Discovery

Huang

Wang

Huang

et al. 2020

IJMS

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Epidemiological results revealed that there is an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and risks of atherosclerotic cardiovascular disease (ASCVD). Mounting evidence supports that HDLs are atheroprotective, therefore, many therapeutic approaches have been developed to increase HDL cholesterol (HDL-C) levels. Nevertheless, HDL-raising therapies, such as cholesteryl ester transfer protein (CETP) inhibitors, failed to ameliorate cardiovascular outcomes in clinical trials, thereby casting doubt on the treatment of cardiovascular disease (CVD) by increasing HDL-C levels. Therefore, HDL-targeted interventional studies were shifted to increasing the number of HDL particles capable of promoting ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux. One such approach was the development of reconstituted HDL (rHDL) particles that promote ABCA1-mediated cholesterol efflux from lipid-enriched macrophages. Here, we explore the manipulation of rHDL nanoparticles as a strategy for the treatment of CVD. In addition, we discuss technological capabilities and the challenge of relating preclinical in vivo mice research to clinical studies. Finally, by drawing lessons from developing rHDL nanoparticles, we also incorporate the viabilities and advantages of the development of a molecular imaging probe with HDL nanoparticles when applied to ASCVD, as well as gaps in technology and knowledge required for putting the HDL-targeted therapeutics into full gear.

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“…As it was mentioned earlier in this review, infusions of recombinant ApoA-I Milano have been shown to cause a significant regression of coronary atherosclerosis in patients with acute coronary syndrome (ACS), 60 but manufacturing difficulties and contamination from host-derived proteins delayed subsequent clinical development of the product. 78 Notwithstanding, in a pilot trial, MDCO-216 (a recently manufactured recombinant ApoA-I Milano without contamination by host-derived proteins) did not produce plaque regression in statin-treated patients following an ACS, 79 and the sponsor company abandoned its further development.…”

Section: Therapeutic Strategies Favorably Affecting Hdl-c Levels And/mentioning

confidence: 99%

Primary genetic disorders affecting high density lipoprotein (HDL)

Kosmas¹,

Silverio²,

Sourlas³

et al. 2018

DIC

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There is extensive evidence demonstrating that there is a clear inverse correlation between plasma high density lipoprotein cholesterol (HDL-C) concentration and cardiovascular disease (CVD). On the other hand, there is also extensive evidence that HDL functionality plays a very important role in atheroprotection. Thus, genetic disorders altering certain enzymes, lipid transfer proteins, or specific receptors crucial for the metabolism and adequate function of HDL, may positively or negatively affect the HDL-C levels and/or HDL functionality and subsequently either provide protection or predispose to atherosclerotic disease. This review aims to describe certain genetic disorders associated with either low or high plasma HDL-C and discuss their clinical features, associated risk for cardiovascular events, and treatment options.

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Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial

Abstract: ClinicalTrials.gov Identifier: NCT02678923.

Cited by 148 publications

References 34 publications

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

Roles of Reconstituted High-Density Lipoprotein Nanoparticles in Cardiovascular Disease: A New Paradigm for Drug Discovery

Primary genetic disorders affecting high density lipoprotein (HDL)

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