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

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...

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Autores principales:	Rhogerry Deshycka, Valentino Sudaryo, Nai-Jia Huang, Yushu Xie, Liyan Y. Smeding, Moon Kyung Choi, Hidde L. Ploegh, Harvey F. Lodish, Novalia Pishesha
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6e2cb9ebe8ff46288add6d9019ba5414
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spelling	oai:doaj.org-article:6e2cb9ebe8ff46288add6d9019ba54142021-11-11T07:14:46ZEngineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity1932-6203https://doaj.org/article/6e2cb9ebe8ff46288add6d9019ba54142021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565730/?tool=EBIhttps://doaj.org/toc/1932-6203Low 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.Rhogerry DeshyckaValentino SudaryoNai-Jia HuangYushu XieLiyan Y. SmedingMoon Kyung ChoiHidde L. PloeghHarvey F. LodishNovalia PisheshaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rhogerry Deshycka Valentino Sudaryo Nai-Jia Huang Yushu Xie Liyan Y. Smeding Moon Kyung Choi Hidde L. Ploegh Harvey F. Lodish Novalia Pishesha Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
description	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.
format	article
author	Rhogerry Deshycka Valentino Sudaryo Nai-Jia Huang Yushu Xie Liyan Y. Smeding Moon Kyung Choi Hidde L. Ploegh Harvey F. Lodish Novalia Pishesha
author_facet	Rhogerry Deshycka Valentino Sudaryo Nai-Jia Huang Yushu Xie Liyan Y. Smeding Moon Kyung Choi Hidde L. Ploegh Harvey F. Lodish Novalia Pishesha
author_sort	Rhogerry Deshycka
title	Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
title_short	Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
title_full	Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
title_fullStr	Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
title_full_unstemmed	Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity
title_sort	engineered red blood cells carrying pcsk9 inhibitors persistently lower ldl and prevent obesity
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/6e2cb9ebe8ff46288add6d9019ba5414
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Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity

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