{"id":14964,"date":"2019-11-04T14:24:15","date_gmt":"2019-11-04T13:24:15","guid":{"rendered":"https:\/\/cri1149.fr\/?post_type=publications&#038;p=14964"},"modified":"2025-09-11T16:48:02","modified_gmt":"2025-09-11T14:48:02","slug":"erythroid-progenitor-targeted-gene-therapy-using-bifunctional-tfr1-ligand-peptides-in-human-erythropoietic-protoporphyria","status":"publish","type":"publication","link":"https:\/\/cri1149.fr\/en\/publication\/erythroid-progenitor-targeted-gene-therapy-using-bifunctional-tfr1-ligand-peptides-in-human-erythropoietic-protoporphyria\/","title":{"rendered":"Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria."},"content":{"rendered":"","protected":false},"featured_media":0,"template":"","meta":{"_acf_changed":false,"_EventAllDay":false,"_EventTimezone":"","_EventStartDate":"","_EventEndDate":"","_EventStartDateUTC":"","_EventEndDateUTC":"","_EventShowMap":false,"_EventShowMapLink":false,"_EventURL":"","_EventCost":"","_EventCostDescription":"","_EventCurrencySymbol":"","_EventCurrencyCode":"","_EventCurrencyPosition":"","_EventDateTimeSeparator":"","_EventTimeRangeSeparator":"","_EventOrganizerID":[],"_EventVenueID":[],"_OrganizerEmail":"","_OrganizerPhone":"","_OrganizerWebsite":"","_VenueAddress":"","_VenueCity":"","_VenueCountry":"","_VenueProvince":"","_VenueState":"","_VenueZip":"","_VenuePhone":"","_VenueURL":"","_VenueStateProvince":"","_VenueLat":"","_VenueLng":"","_VenueShowMap":false,"_VenueShowMapLink":false},"category_publication":[],"class_list":["post-14964","publication","type-publication","status-publish","hentry"],"acf":{"numero_de_publication":"Am J Hum Genet.","date_de_publication":"20190207","numero_doi":"","equipe":[124],"auteurs-liste":[{"texte_libre":false,"auteur-lien":13203,"auteur-text":""},{"texte_libre":false,"auteur-lien":13115,"auteur-text":""},{"texte_libre":false,"auteur-lien":13104,"auteur-text":""},{"texte_libre":false,"auteur-lien":13113,"auteur-text":""},{"texte_libre":false,"auteur-lien":13202,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":" Oustric V"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Poli A"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Lacap\u00e8re JJ"},{"texte_libre":false,"auteur-lien":13125,"auteur-text":""},{"texte_libre":false,"auteur-lien":13142,"auteur-text":""},{"texte_libre":false,"auteur-lien":13094,"auteur-text":""},{"texte_libre":false,"auteur-lien":13139,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Lenglet H"},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Simonin S"},{"texte_libre":false,"auteur-lien":13060,"auteur-text":""},{"texte_libre":false,"auteur-lien":13128,"auteur-text":""},{"texte_libre":false,"auteur-lien":13080,"auteur-text":""}],"auteurs-manuel":"","liens_externes":null,"liens":[{"lien":"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30712775"}],"paragraphe":"<h3 style=\"text-align: justify;\">Abstract<\/h3>\r\n<div class=\"\">\r\n<p style=\"text-align: justify;\">Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P<sub>1<\/sub>-9R) including a TFR1-targeting peptide coupled to a nine-arginine cell-penetrating peptide (CPP) that facilitates the release of the AON from TFR1 in endosomal vesicles. We demonstrated that the P<sub>1<\/sub>-9R\/V1 nanocomplex promotes the efficient and prolonged redirection of splicing towards the physiological splice site and subsequent normalization of WT FECH mRNA and protein levels. Finally, the P<sub>1<\/sub>-9R\/V1 nanocomplex increases WT FECH mRNA production and significantly decreases PPIX accumulation in primary cultures of differentiating erythroid progenitors from an overt EPP-affected individual. P<sub>1<\/sub>-9R is a method designed to target erythroid progenitors and represents a potentially powerful tool for the in\u00a0vivo delivery of therapeutic DNA in many erythroid disorders.<\/p>\r\n<\/div>","paragraphe_en":"","documents":null},"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.4 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria. - CRI<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/cri1149.fr\/publication\/erythroid-progenitor-targeted-gene-therapy-using-bifunctional-tfr1-ligand-peptides-in-human-erythropoietic-protoporphyria\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria. - 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