Sangam: A Confluence of Knowledge Streams

Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity

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dc.contributor Massachusetts Institute of Technology. Department of Biology
dc.creator Deshycka, Rhogerry
dc.creator Sudaryo, Valentino
dc.creator Huang, Nai-Jia
dc.creator Xie, Yushu
dc.creator Smeding, Liyan Y
dc.creator Choi, Moon Kyung
dc.creator Ploegh, Hidde L
dc.creator Lodish, Harvey F
dc.creator Pishesha, Novalia
dc.date 2022-12-16T17:19:10Z
dc.date 2022-12-16T17:19:10Z
dc.date 2021
dc.date 2022-12-16T17:11:55Z
dc.date.accessioned 2023-02-17T20:25:21Z
dc.date.available 2023-02-17T20:25:21Z
dc.identifier https://hdl.handle.net/1721.1/146897
dc.identifier Deshycka, Rhogerry, Sudaryo, Valentino, Huang, Nai-Jia, Xie, Yushu, Smeding, Liyan Y et al. 2021. "Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity." PLoS ONE, 16 (11).
dc.identifier.uri http://localhost:8080/xmlui/handle/CUHPOERS/242563
dc.description <jats:p>Low plasma levels of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) are associated with decreased low-density lipoprotein (LDL) cholesterol and a reduced risk of cardiovascular disease. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of LDL receptors (LDLR), very low-density lipoprotein receptors (VLDLR), apolipoprotein E receptor 2 (ApoER2), and lipoprotein receptor–related protein 1 (LRP1) and accelerates their degradation, thus acting as a key regulator of lipid metabolism. Antibody and RNAi—based PCSK9 inhibitor treatments lower cholesterol and prevent cardiovascular incidents in patients, but their high-cost hampers market penetration. We sought to develop a safe, long-term and one-time solution to treat hyperlipidemia. We created a cDNA encoding a chimeric protein in which the extracellular N- terminus of red blood cells (RBCs) specific glycophorin A was fused to the LDLR EGFA domain and introduced this gene into mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). Following transplantation into irradiated mice, the animals produced RBCs with the EGFA domain (EGFA-GPA RBCs) displayed on their surface. These animals showed significantly reduced plasma PCSK9 (66.5% decrease) and reduced LDL levels (40% decrease) for as long as 12 months post-transplantation. Furthermore, the EGFA- GPA mice remained lean for life and maintained normal body weight under a high-fat diet. Hematopoietic stem cell gene therapy can generate red blood cells expressing an EGFA—glycophorin A chimeric protein as a practical and long-term strategy for treating chronic hyperlipidemia and obesity.</jats:p>
dc.format application/pdf
dc.language en
dc.publisher Public Library of Science (PLoS)
dc.relation 10.1371/JOURNAL.PONE.0259353
dc.relation PLoS ONE
dc.rights Creative Commons Attribution 4.0 International license
dc.rights https://creativecommons.org/licenses/by/4.0/
dc.source PLoS
dc.title Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
dc.type Article
dc.type http://purl.org/eprint/type/JournalArticle


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