Current and Future Pharmacologic Options for the Management of Patients Unable to Achieve Low-Density Lipoprotein-Cholesterol Goals with Statins

Harchaoui, Karim El; Akdim, Fatima; Stroes, Erik S.G.; Trip, Mieke D.; Kastelein, John J.P.

doi:10.2165/00129784-200808040-00003

Cited by 24 publications

(10 citation statements)

References 100 publications

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“…Ribose 2′-modification is a staple of nucleic acid therapeutics and figures prominently in drugs approved by the US FDA such as Macugen (Pegaptanib), an extensively 2′-F/OMe-modified 28mer anti-VEGF RNA aptamer for treatment of wet age-related macular degeneration ( 1–3 ), Mipomersen (Kynamro), a 20mer antisense gap-mer with 2′- O -(2-methoxyethyl)- (2′-MOE) modified wings against homozygous familial hypercholesterolemia ( 4 , 5 ), and Nusinersen (Spinraza), another MOE-RNA 18mer that mediates alternative splicing for the treatment of spinal muscular atrophy ( 6 ). Patisiran, an investigative siRNA-based drug for treatment of hereditary transthyretin-mediated ATTR amyloidosis, currently under FDA review, contains the first generation 2′- O -methyl (2′- O Me) modification ( https://www.drugs.com/history/patisiran.html ) ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the synergy of 4′- and 2′-modifications on siRNA nuclease resistance, thermal stability and RNAi activity

Harp

Guenther

Bisbe

et al. 2018

Nucleic Acids Research

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Chemical modification is a prerequisite of oligonucleotide therapeutics for improved metabolic stability, uptake and activity, irrespective of their mode of action, i.e. antisense, RNAi or aptamer. Phosphate moiety and ribose C2′/O2′ atoms are the most common sites for modification. Compared to 2′-O-substituents, ribose 4′-C-substituents lie in proximity of both the 3′- and 5′-adjacent phosphates. To investigate potentially beneficial effects on nuclease resistance we combined 2′-F and 2′-OMe with 4′-Cα- and 4′-Cβ-OMe, and 2′-F with 4′-Cα-methyl modification. The α- and β-epimers of 4′-C-OMe-uridine and the α-epimer of 4′-C-Me-uridine monomers were synthesized and incorporated into siRNAs. The 4′α-epimers affect thermal stability only minimally and show increased nuclease stability irrespective of the 2′-substituent (H, F, OMe). The 4′β-epimers are strongly destabilizing, but afford complete resistance against an exonuclease with the phosphate or phosphorothioate backbones. Crystal structures of RNA octamers containing 2′-F,4′-Cα-OMe-U, 2′-F,4′-Cβ-OMe-U, 2′-OMe,4′-Cα-OMe-U, 2′-OMe,4′-Cβ-OMe-U or 2′-F,4′-Cα-Me-U help rationalize these observations and point to steric and electrostatic origins of the unprecedented nuclease resistance seen with the chain-inverted 4′β-U epimer. We used structural models of human Argonaute 2 in complex with guide siRNA featuring 2′-F,4′-Cα-OMe-U or 2′-F,4′-Cβ-OMe-U at various sites in the seed region to interpret in vitro activities of siRNAs with the corresponding 2′-/4′-C-modifications.

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Section: Introductionmentioning

confidence: 99%

Structural basis for the synergy of 4′- and 2′-modifications on siRNA nuclease resistance, thermal stability and RNAi activity

Harp

Guenther

Bisbe

et al. 2018

Nucleic Acids Research

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“…Several novel therapies have been developed recently to lower LDL-C in homozygous and heterozygous FH patients [57-65,211]. However, their major drawback is the need for life-long repeated administration in a similar manner to conventional pharmacological drugs.…”

Section: Resultsmentioning

confidence: 99%

“…Several novel therapeutic approaches have also been developed recently to lower LDL-C, either as monotherapy or in combination with statins [57] including; squalene synthase inhibitors [58], microsomal triglyceride transfer protein inhibitors [59,60], siRNA for PCSK9 [61] or for apolipoprotein B-100 [62] silencing, antisense PCSK9 [63], and antisense apolipoprotein B-100 (more commonly known as Mipomersen sodium (ISIS 301012)) [64,65]. …”

Section: Clinical Management Of Fhmentioning

confidence: 99%

LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives

Al-Allaf¹,

Coutelle²,

Waddington³

et al. 2010

Int Arch Med

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Coronary artery diseases (CAD) inflict a heavy economical and social burden on most populations and contribute significantly to their morbidity and mortality rates. Low-density lipoprotein receptor (LDLR) associated familial hypercholesterolemia (FH) is the most frequent Mendelian disorder and is a major risk factor for the development of CAD. To date there is no cure for FH. The primary goal of clinical management is to control hypercholesterolaemia in order to decrease the risk of atherosclerosis and to prevent CAD. Permanent phenotypic correction with single administration of a gene therapeutic vector is a goal still needing to be achieved. The first ex vivo clinical trial of gene therapy in FH was conducted nearly 18 years ago. Patients who had inherited LDLR gene mutations were subjected to an aggressive surgical intervention involving partial hepatectomy to obtain the patient's own hepatocytes for ex vivo gene transfer with a replication deficient LDLR-retroviral vector. After successful re-infusion of transduced cells through a catheter placed in the inferior mesenteric vein at the time of liver resection, only low-level expression of the transferred LDLR gene was observed in the five patients enrolled in the trial. In contrast, full reversal of hypercholesterolaemia was later demonstrated in in vivo preclinical studies using LDLR-adenovirus mediated gene transfer. However, the high efficiency of cell division independent gene transfer by adenovirus vectors is limited by their short-term persistence due to episomal maintenance and the cytotoxicity of these highly immunogenic viruses. Novel long-term persisting vectors derived from adeno-associated viruses and lentiviruses, are now available and investigations are underway to determine their safety and efficiency in preparation for clinical application for a variety of diseases. Several novel non-viral based therapies have also been developed recently to lower LDL-C serum levels in FH patients. This article reviews the progress made in the 18 years since the first clinical trial for gene therapy of FH, with emphasis on the development, design, performance and limitations of viral based gene transfer vectors used in studies to ameliorate the effects of LDLR deficiency.

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“…For example, proprotein convertase subtilisin/kexin type 9 (PCSK9), which inhibits the recycling of the LDL receptor [37][38][39]; squalene synthase [38,39]; 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase, HMGCR) [40,41]; and Apo B, which is related to cholesterol synthesis, are all logical targets for gene therapy. The present study focused on Apo B, which is critical for LDL synthesis and metabolism.…”

Section: Discussionmentioning

confidence: 99%

Efficient reduction of serum cholesterol by combining a liver-targeted gene delivery system with chemically modified apolipoprotein B siRNA

Kang

Tachibana

Obika

et al. 2012

Journal of Controlled Release

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Current and Future Pharmacologic Options for the Management of Patients Unable to Achieve Low-Density Lipoprotein-Cholesterol Goals with Statins

Cited by 24 publications

References 100 publications

Structural basis for the synergy of 4′- and 2′-modifications on siRNA nuclease resistance, thermal stability and RNAi activity

Structural basis for the synergy of 4′- and 2′-modifications on siRNA nuclease resistance, thermal stability and RNAi activity

LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives

Efficient reduction of serum cholesterol by combining a liver-targeted gene delivery system with chemically modified apolipoprotein B siRNA

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