Lipoprotein(a) as a Stroke Biomarker: Pathophysiological Pathways and Therapeutic Implications DOI Open Access

Elias Panagiotopoulos,

Lina Palaiodimou, Aikaterini Theodorou

et al.

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(9), P. 2990 - 2990

Published: April 25, 2025

Lipoprotein(a) [Lp(a)] has attracted widespread interest as a potential biomarker for cerebrovascular diseases due to its genetically determined and stable plasma concentration throughout life. Lp(a) exhibits pro-atherogenic pro-thrombotic properties that contribute vascular pathology in both extracranial intracranial vessels. Elevated levels are strongly associated with large-artery atherosclerotic stroke, while data on role other ischemic subtypes hemorrhagic stroke remains limited inconsistent. Recent advances Lp(a)-lowering therapies, such antisense oligonucleotides RNA-based agents, have demonstrated significant efficacy reducing levels. These prompted increasing research into their application the prevention treatment of diseases, aiming determine whether reduction may translate reduced risk atherosclerosis. This narrative review summarizes current evidence association between focusing utility patient stratification. It also highlights existing knowledge gaps outlines directions future research, particularly understanding subtype-specific effects evaluating clinical benefits Lp(a)-targeted therapies.

Language: Английский

2024 ESC Guidelines for the management of chronic coronary syndromes DOI Creative Commons
Christiaan Vrints, Felicita Andreotti, Konstantinos C. Koskinas

et al.

European Heart Journal, Journal Year: 2024, Volume and Issue: 45(36), P. 3415 - 3537

Published: Aug. 30, 2024

Language: Английский

Citations

456
A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice DOI
Marlys L. Koschinsky, Archna Bajaj, Michael B. Boffa

et al.

Journal of clinical lipidology, Journal Year: 2024, Volume and Issue: 18(3), P. e308 - e319

Published: April 1, 2024

Language: Английский

Citations

82
C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project DOI
Natalie Arnold, Christopher Blaum, Alina Goßling

et al.

European Heart Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 18, 2024

Abstract Background and Aims Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates association between Lp(a) coronary heart (CHD) in general population. Methods Data from 71 678 participants 8 European prospective population-based cohort studies were used (65 661 without/6017 established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine Gray competing risk-adjusted models calculated according accompanying hsCRP concentration (<2 ≥2 mg/L). Results Among CHD-free individuals, increased levels associated incident irrespective concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] highest vs. lowest fifth distribution 1.45 (1.23–1.72) 1.48 (1.23–1.78) a group <2 mg/L, respectively, no interaction found these two biomarkers on (Pinteraction = 0.82). In those CHD, similar associations seen only among individuals ≥ 2 mg/L [1.34 (1.03–1.76)], whereas there clear future events [1.29 (0.98–1.71)] (highest fifth, models; Pinteraction 0.024). Conclusions While significantly regardless hsCRP, baseline, related recurrent residual risk. These findings might guide adequate selection high-risk patients forthcoming Lp(a)-targeting compounds.

Language: Английский

Citations

23
Primary Prevention of Subclinical Atherosclerosis in Young Adults DOI Creative Commons
Ana Devesa, Borja Ibáñez, Waqas Malick

et al.

Journal of the American College of Cardiology, Journal Year: 2023, Volume and Issue: 82(22), P. 2152 - 2162

Published: Nov. 1, 2023

Language: Английский

Citations

33
Three ‘E’ challenges for siRNA drug development DOI Creative Commons
Shuai Guo, Jun Zhang, Yuanyu Huang

et al.

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 30(1), P. 13 - 24

Published: Nov. 9, 2023

Theoretically, siRNA has the ability to target any gene of interest, potentially addressing disease targets that are 'undruggable' for small molecules and proteins.Currently, there six therapeutics have been approved clinical use, approximately 20 additional candidates progressed late stages investigation.Targeted accumulation cellular uptake (entry), endolysosomal escape (escape), in vivo pharmaceutical performance (efficacy) (three 'E' challenges) most critical bottlenecks drug development.Ligand-conjugated siRNAs promising platforms made a breakthrough robust extrahepatic delivery.Sophisticated appropriate chemical modification may bring astounding breakthroughs stability long-term efficacy modalities. gained extensive attention, date use. Despite being investigated treatment metabolic, cardiovascular, infectious, rare genetic diseases, cancer, central nervous system (CNS) disorders, exist several druggability challenges. Here, we provide insightful discussions concerning these challenges, comprising targeted ('entry'), ('escape'), ('efficacy') – three challenges while also shedding light on development. Moreover, propose strategies hold great potential facilitating translation therapeutics, including exploration diverse ligand-siRNA conjugates, expansion targets, excavation novel geometries, as well development combination therapies. Viewed through prism history, enjoyed over century use earliest developed applied therapeutic modality, proteins antibodies emerged relatively almost half century. Although nucleic acid molecules, approach, had shorter developmental timeline (20–30 years), they already captured significant global attention from industry, emerging third prominent modality [1.Opalinska J.B. Gewirtz A.M. Nucleic-acid therapeutics: basic principles recent applications.Nat. Rev. Drug Discov. 2002; 1: 503-514Crossref PubMed Scopus (504) Google Scholar]. Nucleic drugs still undergoing rapid development, particularly realm RNAi, where their broad profound is increasingly manifest. With this mind, believe coming period will be pivotal era acids, both expanding scope options offering new possibilities field. Compared with traditional antibodies, (see Glossary) advantage abundant high success rate, short time, long-lasting efficacy, outstanding attributes platform-based modalities [2.Hopkins A.L. Groom C.R. The druggable genome.Nat. 727-730Crossref (2776) Scholar, 3.Wu S.Y. et al.RNAi therapies: drugging undruggable.Sci. Transl. Med. 2014; 6240ps7Crossref (216) 4.Finan C. al.The genome support identification validation development.Sci. 2017; 9eaag1166Crossref (312) Currently, (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, Rivfloza) successfully commercialized [5.Guo S. al.Membrane-destabilizing ionizable lipid empowered imaging-guided delivery cancer treatment.Exploration. 2021; 35-49Crossref (103) 6.Hu B. al.Therapeutic siRNA: state art.Signal Transduct. Target. Ther. 2020; 5: 101Crossref (617) 7.Zhang M. Huang Y. development.Trends Mol. 2022; 28: 892-893Abstract Full Text PDF (10) application prospects practice, faces (Figure 1). In opinion article, elaborate current status future summarize encountered field, series circumventing strategies. By insights inspiration, article seeks valuable guidance scientific communities alike. years, therapy shown immense numerous candidate preclinical research [8.Zogg H. al.Current advances RNA human diseases.Int. J. Sci. 23: 2736Crossref (65) Scholar,9.Forgham al.Keeping up COVID's could siRNA-based antivirals part answer?.Exploration. 220220012Crossref (4) As August 2023, globally 15 investigational Phase 2 or later (Table 1), covering wide range areas diseases extending common diseases. Leading companies expanded focus encompass popular disorders such metabolic cardiovascular disease, hepatitis B, cancer. For instance, ALN-AGT (NCT04936035i, NCT05103332ii, randomized) currently hypertension trials [10.Huang S.A. al.Safety tolerability ALN-AGT, an interference targeting hepatic angiotensinogen synthesis, hypertensive patients during sodium depletion irbesartan coadministration.Circulation. 144A11276Google Olpasiran (NCT05581303iii, intended treat atherosclerotic plaques 3 study [11.Malick W.A. al.Clinical trial design lipoprotein(a)-lowering JACC Focus Seminar 2/3.J. Am. Coll. Cardiol. 2023; 81: 1633-1645Crossref (9) SLN360 (NCT05537571iv, randomized), lipid-lowering siRNA, investigation. RBD1016 (NCT05961098v, N-acetylgalactosamine (GalNAc)-conjugated start Europe. STP705 STP707 two transforming growth factor beta 1 (TGF-β1) cyclooxygenase (COX-2) formulated peptide nanoparticles (PNPs). was locally administered diseased tissue situ squamous cell carcinoma (isSCC) (NCT04844983vi, 2, basal (BCC) (NCT04669808vii, non-randomized), (NCT05037149viii, 1, non-randomized) intravenously injected into body solid tumors fibrotic liver primary sclerosing cholangitis (PSC).Table 1Selected late-stage therapeuticsDrug nameTarget geneDelivery technologyIndicationSponsorPhase NCT numberAdministration routeaAbbreviations: i.d., intradermal injection; i.t., intratracheal administration; ita, intratumoral i.v., intravenous o.a., ophthalmic s.c., subcutaneous injection.PatisiranTransthyretin (TTR)L NPsPolyneuropathy hereditary TTR-mediated amyloidosis (hATTR)AlnylamApprovedi.v.GivosiranAminolevulinate synthase (ALAS1)GalNAc-siRNA conjugateAcute porphyria (AHP)AlnylamApproveds.c.LumasiranHydroxyacid oxidase (HAO1)GalNAc-siRNA conjugatePrimary hyperoxaluria type (PH1)AlnylamApproveds.c.InclisiranProprotein convertase subtilisin/kexin 9 (PCSK9)GalNAc-siRNA conjugateHypercholesterolemiaAlnylam, Medicine Company, NovartisApproveds.c.VutrisiranTTRGalNAc-siRNA conjugatePolyneuropathy hATTR amyloidosisAlnylamApproveds.c.RivflozaLactate dehydrogenase A (LDHA)GalXC™ RNAi platformPH1Novo NordiskApproveds.c.Olpasiran, AMG 890, ARO-LPAApolipoprotein (APO) A1 (APOA1), Lp(a)GalNAc-siRNA conjugateCardiovascular diseaseAmgen, ArrowheadPhase NCT04270760xviiiPhase 3, NCT05581303iiis.c.ARO-APOC3APOC3GalNAc-siRNA conjugateType I hyperlipoproteinemia, hypertriglyceridemia, congenital metabolism disordersArrowheadPhase NCT05089084xixs.c.Tivanisiran, SYL1001Transient receptor cation channel subfamily V member (TRPV1)None (unmodified, carrier-free)Dry eye Sjögren's syndromeSylentisPhase NCT03108664xii NCT04819269xiiio.a.AOC 1020Double homeobox 4 (DUX4)Antibody-siRNA conjugateFSHDAvidity BiosciencesPhase NCT05747924xxi.v.SLN360APOA1, atherosclerosis, Lp(a)SilencePhase NCT05537571ivs.c.SLN-124Transmembrane serine protease 6 (TMPRSS6)GalNAc-siRNA conjugatePolycythemia veraSilencePhase 1/2, NCT05499013xxis.c.Zilebesiran, ALN-AGTAngiotensinogen (AGT)GalNAc-siRNA conjugateHypertensionAlnylamPhase NCT04936035i, NCT05103332iis.c.ALN-HSDHydroxysteroid 17-beta 13 (HSD17B13)GalNAc-siRNA conjugateNASHAlnylam, RegeneronPhase NCT05519475xxiis.c.OLX10010Connective (CTGF)Cell-penetrating asymmetric (cp-asiRNA)Hypertrophic scarringOlix, Alira HealthPhase NCT04877756xxiiii.d.XalnesiranHBV geneGalNAc-siRNA conjugateHepatitis B virus (HBV)Dicerna, Novo NordiskPhase NCT04225715xxivs.c.RBD1016HBV conjugateHBVRibo Life Science LtdPhase NCT05961098vs.c.SYL1801NOTCH regulated ankyrin repeat protein (NRARP)NoneWet macular degeneration, neovascular age-related degenerationSylentisPhase NCT05637255xxvo.a.SYL040012Adrenoceptor (ADRB2)NoneOpen-angle glaucomaSylentisPhase NCT02250612xxvi, NCT01739244 xxviio.a.STP705COX-2, TGF-β1PNPsBCC, intraepidermal SCC, skin SCC (isSCC, keloid), keloidSirnaomicsPhase NCT04669808vii, NCT04844983vi, NCT04844840xxviiis.c., itasiG12D-LODERKRAS proto-oncogene, GTPase (KRAS)LODER®Pancreatic ductal adenocarcinomaSilenseedPhase NCT01676259xxixitaa Abbreviations: injection. Open table tab From product pipeline perspective, notable lies its [12.Weng innovative biotechnological evolution.Biotechnol. Adv. 2019; 37: 801-825Crossref (185) 13.Lu al.Photoactivatable silencing extracellular vesicle (PASEV) sensitizes immunotherapy.Adv. Mater. 34e2204765Crossref (22) 14.Zhang al.Conscription immune cells by light-activatable NK-derived exosome (LASNEO) synergetic tumor eradication.Adv. (Weinh.). 9e2201135Google 15.Guo al.A polyethyleneimine-decorated FeOOH nanoparticle efficient delivery.Chin. Chem. 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ALN-APP (NCT05231785ix, intrathecally amyloid precursor (APPs) Alzheimer's (AD) [23.Mishra N. al.Role nanocarriers neurodegenerative diseases.Drug 27: 1431-1440Crossref (14) Scholar] cerebral angiopathy (CAA) [24.Nat. Biotechnol. 40: 1439-1440Crossref (2) Recently, ongoing attained positive mid-term results single-drug dose escalation trialx. ARO-SOD1 (NCT05949294xi, superoxide dismutase (SOD1) amyotrophic lateral sclerosis (ALS) caused SOD1 mutations, which study. addition, clinically therapies progressing towards other tissues, eye, muscle, lung, fat. Tivanisiran (SYL1001) (NCT03108664xii, NCT04819269xiii, dry disease. ARO-DUX4xiv (Phase 1/2) facioscapulohumeral muscular dystrophy (FSHD) submitted trials. ARO-MUC5AC (NCT05292950xv, ARO-RAGE (NCT05276570xvi, ARO-MMP7 (NCT05537025xvii, 1/2a, pulmonary It noteworthy administration frequency achieved historic breakthrough. enhanced stabilization enables durable repression effect sequence-dependent off-target effects. example, Leqvio requires only twice first months, followed treatments every effectively manage hypercholesterolemia mixed dyslipidemia. There 100 worldwide engaged 30 them specifically focusing Informa Pharma Intelligence's Biomedtracker recorded, 200 siRNA/RNAi-based Since 2016, total 14 antisense oligonucleotides (ASOs) commercialization. Additionally, field oligonucleotide witnessed activity terms mergers acquisitions. licensing agreements years fields neurological Representative include (LNP), GalNAc-siRNA conjugates (GalAheadTM, PDoV-GalNAc, etc.), GEMINI™, TRiM™, PNPs, RIBO-GalSTAR®, RIBO-OncoSTAR [25.Gao My together Journal Oral Pathology Medicine.J. Pathol. 52: 324-327Crossref (1) IKARIA™ established develop long-acting siRNA. progress research, some remain should overcome. Specifically, (entry, escape, efficacy) issues limit challenge achieve enrichment organs/tissues effective internalization 1A). Due large size anionic charge, unmodified naked display low bioavailability, half-life minutes [26.Gao formulation biodistribution mice.Mol. 2009; 17: 1225-1233Abstract (235) Nanocarrier-encapsulated typically bound serum proteins, leading reticuloendothelial (RES) phagocytic clearance [27.Blanco E. al.Principles overcoming biological barriers delivery.Nat. 2015; 33: 941-951Crossref (4580) can rapidly degraded nucleases phosphatase present plasma, cytoplasm. After systemic clearance, must cross endothelium capillaries enter tissue, challenging due adhesion tight junctions. passively accumulate porous sites delivering agents parts beyond organs preferentially absorb crossing blood–brain barrier (BBB) blood–retinal barrier, [28.Pecot C.V. al.RNA clinic: directions.Nat. Cancer. 11: 59-67Crossref (701) second how lysosomal escape. endocytosis, less than 1% endosome, passive rate 0.01% [29.Dowdy S.F. Overcoming 35: 222-229Crossref (706) asialoglycoprotein (ASGPR) exception, expression levels 500 000 higher recycle time min [30.Fakhr al.Precise design: key point competent silencing.Cancer Gene 2016; 73-82Crossref (113) Sufficient cytoplasm hepatocytes treatment. While provides hope RNAi-based therapies, remains unresolved issue types cells. surface receptors 10 000–100 less, times longer 90 [31.Juliano R.L. oligonucleotides.Nucleic Acids Res. 44: 6518-6548Crossref (600) 1B). result degradation it observed minuscule fraction endocytosed conjugate at given moment [32.Brown al.Investigating pharmacodynamic durability conjugates.Nucleic 48: 11827-11844Crossref (116) Remarkably, endosomally entrapped serve depot, thereby sustaining long single-dose response duration, offset substantial proportion fail penetrate Consequently, release endosomes indeed inhibits broader needs counterbalance maintain depot extent, ensuring sustained responses extended period. To date, attempts enhance using modified pH sensitivity, ion-penetrating agents, chloroquine-like lysosomotropic pore-forming peptides melittin [33.Hou K.K. entrapment melittin.Biotechnol. 931-940Crossref (60) dodecylphosphocholine (DPC), and/or GalNAc-conjugated melittin-like (NAG-MLP) not fully resolved relationship between cytotoxicity increased requirement good stability, effects, safety. viral vectors toxic side effects [34.Deyle D.R. genome-wide map adeno-associated virus-mediated targeting.Nat. Struct. Biol. 969-975Crossref (11) Scholar,35.Zhu al.Nanoparticle-mediated corneal neovascularization treatments: toward generation systems.Chin. 34107648Crossref (5) mainly limited studies. Chemically synthesized carrier systems cationic lipids [36.Meraz I.M. al.Adjuvant liposomes presenting MPL IL-12 induce death, suppress growth, alter phenotype murine model breast cancer.Mol. Pharm. 3484-3491Crossref (20) inorganic [37.Mohammapdour R. Ghandehari Mechanisms products.Adv. Deliv. 180114022Crossref (31) apoptosis inflammation vivo. ensure ease production, quality control, transport large-scale applications [38.Humphreys S.C. al.Considerations recommendations assessment plasma binding drug–drug interactions therapeutics.Nucleic 50: 6020-6037Crossref (18) widely used mouse studies toxicity evaluation model, dose–response obtained models cannot directly beings. Non-primate often lack sufficient overlap genomic sequences humans predict so necessary expand non-human primate (NHP) or, choice, disease-related organoids [39.Pauli al.Personalized vitro guide precision medicine.Cancer 7: 462-477Crossref (651) Oligonucleotides without normally unstable easily bloodstream. exogenous immunogenicity cause reactions body. technological breakthroughs, modifications [e.g., phosphorothioate (PS) backbone, ribose, end strand] reduce/erase [40.Khvorova A. Watts J.K. evolution utility.Nat. 238-248Crossref (731) 41.Ge Q. al.Effects potency, immunostimulatory properties shRNAs.RNA. 2010; 16: 118-130Crossref (57) 42.Robbins al.2′-O-methyl-modified RNAs act TLR7 antagonists.Mol. 2007; 15: 1663-1669Abstract (255) improving 'efficacy' [43.Ray al.Two inclisiran elevated LDL cholesterol.N. Engl. 382: 1507-1519Crossref (702) Scholar,44.Desai A.S. al.Zilebesiran, agent hypertension.N. 389: 228-238Crossref (15) 1C). Through sophisticated modification, 99% persistent existence body, allowing low-dose quarterly, semiannual, even annual dosing [45.Fitzgerald K. highly inhibitor PCSK9.N. 376: 41-51Crossref (290) evolutionary history fascinating area deserves further comprehensive exploration. However, despite achievements, remain. modification-induced specificity enhancement reduce unexpected adverse [46.Jackson Linsley P.S. Recognizing application.Nat. 9: 57-67Crossref (793) Scholar,47.Sun al.Enhancing encapsulation.Molecules. 22: 1724Crossref (35) 1D). (including induced toxicity) need carefully assessed More importantly, patent families significantly contributed intellectual property landscape drugs. WO2016028649 outlines geometry divides strands distinct regions defined specific ranges nucleotide counts, providing structures physicochemical monomers each region. WO2013074974 describes dsRNA duplex motifs identical consecutive nucleotides one strands, near cleavage site. WO2018185241 focuses positions 5′ strand sense strand, correspond position 11, 13, 11 11–13 strand. These patents pose necessitating establishment unique technologies entities address advance approaches worth Optimizing important direction improve specificity, safety, bioavailability. This includes monomers, patterns, trigger 2A–C ). Traditional involve 2′-O-methylation (2′-OMe), 2′-fluoro-deoxyribonucleotide (2′-F), PS, patterns refine pharmacokinetic safety profiles siRNAs. glycol (GNA) 5′-(E)-vinylphosphonate [5′-(E)-VP] 2B), chemistry (ESC) plus (ESC+) 2A), circular interfering (sciRNAs) [48.Egli Manoharan Chemistry, structure function 51: 2529-2573Crossref Scholar,49.Jahns al.Small potent platform gene-silencing.Nucleic 49: 10250-10264Crossref (7) [50.Khvorova al.Fully Stabilized Asymmetric University Massachusetts, 2016Google Scholar,51.Turanov A.A. modulation placental sFLT1 preeclampsia.Nat. 2018; 36: 1164-1173Crossref (119) divalent scaffold [52.Alterman J.F. throughout system.Nat. 884-894Crossref (104) 2C). now algorithms. Alnylam generations designs,

Language: Английский

Citations

29
The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering DOI Creative Commons
Michelle L. O’Donoghue, Robert S. Rosenson, J. Antonio G. López

et al.

Journal of the American College of Cardiology, Journal Year: 2024, Volume and Issue: 84(9), P. 790 - 797

Published: Aug. 1, 2024

Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) >95%.

Language: Английский

Citations

14
Nucleic acid drugs: recent progress and future perspectives DOI Creative Commons

Xiaoyi Sun,

Sarra Setrerrahmane,

Chencheng Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 29, 2024

Language: Английский

Citations

11
Prevalence of Elevated Lipoprotein(a) and its Association With Subclinical Atherosclerosis in 2.9 Million Chinese Adults DOI
Sailimai Man, Yuangang Zu, Xiaochen Yang

et al.

Journal of the American College of Cardiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

1
The Promise of PCSK9 and Lipoprotein(a) as Targets for Gene Silencing Therapies DOI Creative Commons
Dick C. Chan, Gerald F. Watts

Clinical Therapeutics, Journal Year: 2023, Volume and Issue: 45(11), P. 1034 - 1046

Published: July 29, 2023

High plasma concentrations of LDL and lipoprotein(a) (Lp[a]) are independent causal risk factors for atherosclerotic cardiovascular disease (ASCVD). There is an unmet therapeutic need high-risk patients with elevated levels LDL-C and/or Lp(a). Recent advances in the development nucleic acids gene silencing (ie, triantennary N-acetylgalactosamine conjugated antisense-oligonucleotides [ASOs] small interfering RNA [siRNA]) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) Lp(a) offer effective sustainable therapies.

Language: Английский

Citations

17
Residual cardiovascular risk: When should we treat it? DOI
Francisco Gómez-Delgado, Manuel Raya‐Cruz, Niki Katsiki

et al.

European Journal of Internal Medicine, Journal Year: 2023, Volume and Issue: 120, P. 17 - 24

Published: Oct. 14, 2023

Language: Английский

Citations

17