{"doi":"10.1016/j.jlr.2024.100524","title":"PCSK9 vaccines: a promising new strategy for the treatment of hypercholesterolemia?","abstract":"VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeysJournal of Lipid ResearchVol. 65Issue 2PreviewAtherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a “high-risk” patient population or those who have failed other therapies. Full-Text PDF Open Access Management of elevated LDL-C, a causal risk factor in the development of atherosclerotic cardiovascular disease (ASCVD), has been revolutionized by using inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9). When used in conjunction with statins, PCSK9 inhibitors can markedly lower LDL-C to levels that have not been previously attained with other lipid-lowering medications. Circulating LDL-C is normally cleared from plasma when it taken up by hepatocytes that express the LDL receptor (LDL-R). PCSK9, a secretory protein largely produced by the liver, negatively regulates LDL-C homeostasis by mediating the internalization and degradation of LDL-R. Naturally occurring mutations that increase PCSK9 activity are associated with higher levels of circulating LDL-C, whereas mutations that downregulate PCSK9 lead to low serum LDL-C levels and a lower risk of ASCVD. Currently, two classes of PCSK9 inhibitors have been approved by the US Food and Drug Administration. These include two anti-PCSK9 monoclonal antibodies (mAbs), evolocumab and alirocumab, and an siRNA-based therapeutic, inclisiran. In hypercholesterolemic individuals these drugs can dramatically lower LDL-C levels, often by as much as 60% or more (1Ray K.K. Stoekenbroek R.M. Kallend D. Leiter L.A. Landmesser U. Wright R.S. et al.Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins: prespecified secondary end points in ORION 1.Circulation. 2018; 138: 1304-1316Crossref PubMed Scopus (117) Google Scholar, 2Robinson J.G. Farnier M. Krempf M. Bergeron J. Luc G. Averna M. et al.Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.N. Engl. J. Med. 2015; 372: 1489-1499Crossref PubMed Scopus (1710) Google Scholar, 3Sabatine M.S. Giugliano R.P. Wiviott S.D. Raal F.J. Blom D.J. Robinson J. et al.Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.N. Engl. J. Med. 2015; 372: 1500-1509Crossref PubMed Scopus (1373) Google Scholar). The widespread adoption of these PCSK9 inhibitors, however, has been relatively slow, largely due to their high cost. Consequently, PCSK9 inhibitors are reserved for high-risk patients and for secondary prevention for those patients who fail to achieve target LDL-C levels, using conventional statin-based therapies (4Landmesser U. Chapman M.J. Stock J.K. Amarenco P. Belch J.J.F. Boren J. et al.New prospects for PCSK9 inhibition?.Eur. Heart J. 2018; 39: 2600-2601Crossref PubMed Google Scholar). Another limitation is that anti-PCSK9 mAbs require regular subcutaneous injections every 2–4 weeks, which complicates their utilization and reduces patient adherence. These practical issues have prompted efforts to develop more accessible and/or longer lasting alternatives for inhibiting PCSK9, such as an oral drug inhibitor (5Siddiqui Z. Frishman W. New oral PCSK9 inhibitor: “MK-0616”.Cardiol. Rev. 2024; https://doi.org/10.1097/CRD.0000000000000655Crossref PubMed Google Scholar), a gene editing approach (6Lee R.G. Mazzola A.M. Braun M.C. Platt C. Vafai S.B. Kathiresan S. et al.Efficacy and safety of an investigational single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models.Circulation. 2023; 147: 242-253Crossref PubMed Scopus (41) Google Scholar), and vaccine","journal":"Journal of Lipid Research","year":2024,"id":444197,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":311171,"name":"Alan T. Remaley","orcid":"0000-0003-2473-5549","position":1,"is_corresponding":false},{"id":460622,"name":"Bryce Chackerian","orcid":"0000-0002-5712-4739","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:01:33.526738Z","pmid":"38373655","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}