Lipoprotein(a)—antisense therapy

Vogt, Anja

doi:10.1007/s11789-019-00096-2

Cited by 14 publications

(5 citation statements)

References 50 publications

(54 reference statements)

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“…Some trials and data from registries show that regular apheresis effectively reduces CV events (63). The results of 5 years of prospective follow-up confirmed that Lp(a) apheresis has a lasting effect on the prevention of CV events in patients with hyperlipoproteinemia (a), reducing the mean annual cardiovascular event rate by up to 80% (64,65).…”

Section: Lp(a) Apheresismentioning

confidence: 85%

“…As already mentioned, mipomersen, an ASO which markedly inhibits mRNA of apoB, does not affect the production of apo(a), but could lower Lp(a) by influencing the Lp(a) assembly. The ASO by which we can inhibit apo(a) synthesis in the liver is currently the only available approach for specific Lp(a) lowering (84,85). Being injected subcutaneously, they enter the circulation and bind to plasma proteins, while after entering the liver, they accumulate in the hepatocytes.…”

Section: Emerging Treatment Possibilities With Rna-targeted Therapiesmentioning

confidence: 99%

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Increased cardiovascular risk associated to hyperlipoproteinemia (a) and the challenges of current and future therapeutic possibilities

Fras¹

2019

Anatol J Cardiol

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Increased cardiovascular risk associated with hyperlipoproteinemia (a) and the challenges of current and future therapeutic possibilitiesPopulation, genetic, and clinical studies demonstrated a causative and continuous, from other plasma lipoproteins independent relationship between elevated plasma lipoprotein (a) [Lp(a)] concentration and the development of cardiovascular disease (CVD), mainly those related to atherosclerotic CVD, and calcific aortic stenosis. Currently, a strong international consensus is still lacking regarding the single value which would be commonly used to define hyperlipoproteinemia (a). Its prevalence in the general population is estimated to be in the range of 10%-35% in accordance with the most commonly used threshold levels (>30 or >50 mg/dL). Since elevated Lp(a) can be of special importance in patients with some genetic disorders, as well as in individuals with otherwise controlled major risk factors, the identification and establishment of the proper therapeutic interventions that would lower Lp(a) levels and lead to CVD risk reduction could be very important. The majority of the classical lipidlowering agents (statins, ezetimibe, and fibrates), as well as nutraceuticals (CoQ10 and garlic), appear to have no significant effect on its plasma levels, whereas for the drugs with the demonstrated Lp(a)-lowering effects (aspirin, niacin, and estrogens), their clinical efficacy in reducing cardiovascular (CV) events has not been unequivocally proven yet. Both Lp(a) apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors can reduce the plasma Lp(a) by approximately 20%-30% on average, in parallel with much larger reduction of low-density lipoprotein cholesterol (up to 70%), what puts us in a difficulty to conclude about the true contribution of lowered Lp(a) to the reduction of CV events. The most recent advancement in the field is the introduction of the novel apolipoprotein (a) [apo(a)] antisense oligonucleotide therapy targeting apo(a), which has already proven itself as being very effective in decreasing plasma Lp(a) (by even >90%), but should be further tested in clinical trials. The aim of this review was to present some of the most important accessible scientific data, as well as dilemmas related to the currently and potentially in the near future more widely available therapeutic options for the management of hyperlipoproteinemia (a).

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Section: Lp(a) Apheresismentioning

confidence: 85%

Section: Emerging Treatment Possibilities With Rna-targeted Therapiesmentioning

confidence: 99%

Increased cardiovascular risk associated to hyperlipoproteinemia (a) and the challenges of current and future therapeutic possibilities

Fras¹

2019

Anatol J Cardiol

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“…The general siRNA therapeutic strategy is to load RISC with synthetic antisense (AS) sequences to downregulate a specific target RNA of clinical relevance. Therapeutic targets have included mRNA, pre-mRNA, long noncoding RNA (lncRNA), and viral and bacterial RNA. − Similar to ASOs, RNA target selection is guided by identifying pathological situations; for example, where an overabundance of protein or RNA is expressed, expanded RNA repeats are present, spliceopathy exists, or a genetic mutation in one or both alleles leads to production of a dysfunctional RNA or protein. − …”

Section: Part 1: Therapeutic Strategy and Sar In Drug Developmentmentioning

confidence: 99%

Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development

et al. 2020

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After two decades teetering at the intersection of laboratory tool and therapeutic reality, with two siRNA drugs now clinically approved, this modality has finally come into fruition. Consistent with other emerging modalities, initial proof-of-concept efforts concentrated on coupling pharmacologic efficacy with desirable safety profiles. Consequently, thorough investigations of siRNA absorption, distribution, metabolism, and excretion (ADME) properties are lacking. Advancing ADME knowledge will aid establishment of in vitro–in vivo correlations and pharmacokinetic–pharmacodynamic relationships to optimize candidate selection through discovery and translation. Here, we outline the emerging siRNA design principles and discuss the consequences for siRNA disposition and biotransformation. We propose a conceptual framework for siRNA ADME evaluation, contextualizing the site of biotransformation product formation with PK–PD modulation, and end with a discussion around safety and regulatory considerations and future directions for this modality.

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“…Research in the lipoprotein field has led to the recent development of an antisense oligonucleotide against apo(a), AKCEA-APO(a)-LRx, which selectively decreases Lp(a) concentrations by approximately 80% [28].…”

Section: New Lipid-lowering Treatments Specifically Targeting Lp(a)mentioning

confidence: 99%

Lipoprotein(a), the rediscovered risk factor, or how to get “back to the future”

Sabouret

Angoulvant

Ray

2020

Archives of Cardiovascular Diseases

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Lipoprotein(a)—antisense therapy

Cited by 14 publications

References 50 publications

Increased cardiovascular risk associated to hyperlipoproteinemia (a) and the challenges of current and future therapeutic possibilities

Increased cardiovascular risk associated to hyperlipoproteinemia (a) and the challenges of current and future therapeutic possibilities

Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development

Lipoprotein(a), the rediscovered risk factor, or how to get “back to the future”

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