New Therapeutic Approaches for Familial Hypercholesterolemia

Ajufo, Ezim; Rader, Daniel J.

doi:10.1146/annurev-med-051215-030943

Cited by 22 publications

(17 citation statements)

References 90 publications

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“…However, both agents may cause liver steatosis and are currently only in use as adjunct therapy in homozygous familial hypercholesterolemia 31,[238][239][240][241] . No data are available on cardiovascular outcomes with either lomitapide or mipomersen 242,243 .…”

Section: [H2] Inhibitors Of Vldl Productionmentioning

confidence: 99%

Lipid management in patients with chronic kidney disease

Ferro¹,

Mark²,

Kanbay³

et al. 2018

Nat Rev Nephrol

181

142

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Glomerular filtration rate is inversely associated with cardiovascular disease independent of conventional risk factors. An increased risk of cardiovascular disease is present even at minor levels of renal impairment and the risk is highest in patients with endstage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition, and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease or ESRD have a characteristic lipid pattern of hypertriglyceridemia and low HDL-cholesterol levels but normal LDL-cholesterol levels. In the general population, a clear relationship exists between LDL-cholesterol, coronary heart disease and ischaemic stroke. However, in patients with ESRD, LDL-cholesterol seems to show a negative association [Au: with these outcomes?] at below average LDL-cholesterol levels and a flat or weakly positive association with mortality at higher LDL-cholesterol levels. Overall, the available data suggest that lowering of LDL-cholesterol is beneficial for prevention of major atherosclerotic events in patients with chronic kidney disease and in kidney transplant recipient but is not beneficial in patients requiring dialysis. [Au: I've moved the description of the content of your Review to the end of the introduction as per our journal style. To fully reflect the content of your article, please finish off the abstrace with a couple of sentences relating to novel lipid-lowering therapies and the need for reconsideration of the KDIGO guidelines in the light of new data. We have a limit of 200 words for this section.] [Au: I have highlighted suggestions for glossary terms throughout your manuscript with a [G]. Please provide succinct, one-sentence definitions for these specialist terms.] [H1] Introduction Guidelines regarding the management of lipids in patients with chronic kidney disease (CKD) and especially in those with end-stage renal disease (ESRD) are inconsistent in part owing to important deficiencies in the available data. [Au: Edit OK?] In 2013 KDIGO produced a comprehensive clinical practice guideline for lipid management in CKD 1. [Au: I suggest that we cite your original Table 1 (now Table 3) in the discussion of KDIGO recommendations at the end of the review so that the table is included next to this discussion in the final layout rather than in the introduction to the Review.

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Section: [H2] Inhibitors Of Vldl Productionmentioning

confidence: 99%

Lipid management in patients with chronic kidney disease

Ferro¹,

Mark²,

Kanbay³

et al. 2018

Nat Rev Nephrol

181

142

View full text Add to dashboard Cite

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“…Nonetheless, it is clear already that lncRNAs will emerge as important new therapeutic targets for the treatment of metabolic disorders, including dyslipidemias, hepatosteatosis and atherosclerosis. ASO-based therapies to inhibit mRNAs and lncRNAs are actively being pursued, with mipomersen, the apoB-targeting ASO for treatment of familial hypercholesterolemia leading the way with FDA-approval [63,64]. As the mysteries of lncRNAs continue to be unraveled, parallel improvements of therapeutic tools to target non-coding RNAs in tissue-specific ways will no doubt accelerate the development future RNA-based therapies for diseases in the area of lipid metabolism and beyond.…”

Section: Resultsmentioning

confidence: 99%

Long noncoding RNAs in lipid metabolism

Solingen

Scacalossi

Moore

2018

Current Opinion in Lipidology

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Purpose of review Noncoding RNAs have emerged as important regulators of cellular and systemic lipid metabolism. In particular, the enigmatic class of long noncoding RNAs have been shown to play multifaceted roles in controlling transcriptional and posttranscriptional gene regulation. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in the regulation of lipid metabolism during health and disease. Recent findings Despite comprising the majority of the transcriptionally active regions of the human genome, lncRNA functions remain poorly understood, with fewer than 1% of human lncRNAs functionally characterized. Broadly defined as nonprotein coding transcripts greater than 200 nucleotides in length, lncRNAs execute their functions by forming RNA–DNA, RNA–protein, and RNA–RNA interactions that regulate gene expression through diverse mechanisms, including epigenetic remodeling of chromatin, transcriptional activation or repression, posttranscriptional regulation of mRNA, and modulation of protein activity. It is now recognized that in lipid metabolism, just as in other areas of biology, lncRNAs operate to regulate the expression of individual genes and gene networks at multiple different levels. Summary The complexity revealed by recent studies showing how lncRNAs can alter systemic and cell-type-specific cholesterol and triglyceride metabolism make it clear that we have entered a new frontier for discovery that is both daunting and exciting.

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“…The most common adverse effects of mipomersen, when used continuously for 2 years, are injection-site reactions (98% of patients), flu-like symptoms (65%), and clinically relevant elevations of liver enzymes (13%) 59 . Most studies have also documented significant increases in hepatic fat content (in line with the drug´s mechanism -inhibition of lipoprotein production and secretion by the liver) 3,57,58 . A study of liver biopsies from patients chronically treated with mipomersen showed severe steatosis in most patients (five out of seven), albeit without histological signs of nonalcoholic steatohepatitis.…”

Section: Mipomersenmentioning

confidence: 94%

“…Despite the widespread use of efficacious lipid-modifying therapies, the residual risk of CVD remains unacceptably high 1 . Besides suboptimal control of non-lipid risk factors, our ability to reduce CVD is also constrained by intolerance or poor adherence to statin therapy 2 , limited availability and access to therapies for severe, genetic dyslipidemias 3 , and inconsistent evidence about the benefits of impacting the high-density lipoprotein (HDL)/triglycerides (TG) axis 4 .…”

Section: Introductionmentioning

confidence: 99%

New Biotechnological Treatments for Lipid Disorders

Valencia-Enciso

Mendivil

2018

RIC

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Disorders of lipid and lipoprotein metabolism play a central role in the pathogenesis of atherosclerotic cardiovascular diseases (CVDs). Despite the widespread use of efficacious lipid-modifying therapies, the residual risk of CVD remains unacceptably high. The purpose of this manuscript is to review the application of new technologies in the treatment of lipid disorders. New therapies work mostly at the gene expression level and are, therefore, different from traditional small-molecule drugs that work mainly by inhibiting already synthesized proteins. We will briefly lay out the function of the gene products targeted by the new agents. Then, we will organize our review of new biotechnological treatments by the molecular approach, namely: monoclonal antibodies, antisense oligonucleotides, small-interfering RNAs, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9)-based genome editing. The paper concludes with the description of the current clinical studies and the perspectives for the use of these agents.

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New Therapeutic Approaches for Familial Hypercholesterolemia

Cited by 22 publications

References 90 publications

Lipid management in patients with chronic kidney disease

Lipid management in patients with chronic kidney disease

Long noncoding RNAs in lipid metabolism

New Biotechnological Treatments for Lipid Disorders

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