{"id":2403,"date":"2020-02-28T10:02:49","date_gmt":"2020-02-28T09:02:49","guid":{"rendered":"https:\/\/www.aica3.org\/cms\/?p=2403"},"modified":"2022-01-04T17:28:42","modified_gmt":"2022-01-04T16:28:42","slug":"lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a","status":"publish","type":"post","link":"https:\/\/www.aica3.org\/cms\/en\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/","title":{"rendered":"Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A"},"content":{"rendered":"<div class=\"page\" title=\"Page 1\">\n<div class=\"layoutArea\">\n<div class=\"column\">\n<p>Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A<\/p>\n<div class=\"page\" title=\"Page 1\">\n<div class=\"section\">\n<div class=\"layoutArea\">\n<div class=\"column\">\n<p><strong>Lostal et al., Sci. Transl. Med. 11, eaat6072 (2019) 27 Novembre 2019<\/strong><\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"page\" title=\"Page 1\">\n<div class=\"layoutArea\">\n<div class=\"column\">\n<p><strong>Author: <\/strong><span style=\"font-size: inherit;\">William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, <\/span><span style=\"font-size: inherit;\">Nathalie Bourg1, Heather Best1, John Edward Smith, Jochen Gohlke, Guillaume Corre, <\/span><span style=\"font-size: inherit;\">Xidan Li, Zaher Elbeck, Ralph Kn\u00f6ll, Jack-Yves Deschamps, Henk Granzier, Isabelle Richard<\/span><\/p>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"page\" title=\"Page 1\">\n<div class=\"layoutArea\">\n<div class=\"column\">\n<p>Lateral muscular dystrophy type 2A (LGMD 2A or LGMDR1) is a neuromuscular disease caused by mutations in the calpain 3 (CAPN3) gene . Preliminary experiments of calpain3 gene transfer mediated by adenoviral-associated vectors (AAVs) have shown cardiotoxicity with ectopic expression of the calpain 3 transgene.<\/p>\n<p>In this study, we performed a preliminary dose study in a mouse model of severe muscular dystrophy, double knock out for both calpain 3 and dysferlin.<\/p>\n<p>We also evaluated the safety and biodistribution of administration of the AAV9-desmin-hCAPN3a vector to nonhuman primates (NHPs) with a dose of 3 X 10 13 viral genome\/kg.<\/p>\n<p>Administration of the vector caused no detectable adverse effects or toxicity in NHPs. Of note, expression of the transgene did not cause any cardiac morphological or functional abnormalities in the injected animals and achieved therapeutic expression in skeletal muscle.<\/p>\n<p>Further studies about the cause of cardiotoxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest a species-specific splicing of titin.<\/p>\n<p>Mice have reduced calpain-3 buffering capacity in comparison to nonhuman primates and humans.<\/p>\n<p>Our studies highlight a complex interaction between calpain-3 and titin and demonstrate an effective and safe role for systemic delivery of calpain-3 via an adenoviral vector (AAV9-desmin-hCAPN3a) in nonhuman primates, providing adequate support for potential calpain-3 gene therapy in humans.<\/p>\n<table style=\"width: 354.6875px;\">\n<tbody>\n<tr style=\"height: 100.625px;\">\n<td style=\"width: 75px; height: 100.625px; vertical-align: middle;\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-1944\" src=\"https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf-150x150.png\" alt=\"\" width=\"59\" height=\"59\" srcset=\"https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf-150x150.png 150w, https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf-49x49.png 49w, https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf.png 256w\" sizes=\"(max-width: 59px) 100vw, 59px\" \/><\/td>\n<td style=\"width: 302.6875px; height: 100.625px; vertical-align: middle;\">\n<h3><a href=\"https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2020\/02\/LostalRichard2029.pdf\"> Download Full Article<\/a><\/h3>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<\/div>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A Lostal et al., Sci. Transl. Med. 11, eaat6072 (2019) 27 Novembre 2019 Autore: William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg1, Heather Best1, John Edward Smith, Jochen [&hellip;]<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":""},"categories":[34,33],"tags":[],"class_list":["post-2403","post","type-post","status-publish","format-standard","hentry","category-articoli-scientifici","category-ricerca-e-pubblicazioni"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A - AICa3 - ETS - Associazione Italiana Calpaina 3<\/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:\/\/www.aica3.org\/cms\/en\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A - AICa3 - ETS - Associazione Italiana Calpaina 3\" \/>\n<meta property=\"og:description\" content=\"Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A Lostal et al., Sci. 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Med. 11, eaat6072 (2019) 27 Novembre 2019 Autore: William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg1, Heather Best1, John Edward Smith, Jochen [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.aica3.org\/cms\/en\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/\" \/>\n<meta property=\"og:site_name\" content=\"AICa3 - ETS - Associazione Italiana Calpaina 3\" \/>\n<meta property=\"article:publisher\" content=\"http:\/\/www.facebook.com\/pages\/AICa3-Associazione-Italiana-Calpaina-3\/119599211561350\" \/>\n<meta property=\"article:published_time\" content=\"2020-02-28T09:02:49+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2022-01-04T16:28:42+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf-150x150.png\" \/>\n<meta name=\"author\" content=\"admin\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"admin\" \/>\n\t<meta name=\"twitter:label2\" content=\"Estimated reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\\\/\"},\"author\":{\"name\":\"admin\",\"@id\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/#\\\/schema\\\/person\\\/8a5e19b3ab1d1aa2190043f3ddb89aa2\"},\"headline\":\"Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A\",\"datePublished\":\"2020-02-28T09:02:49+00:00\",\"dateModified\":\"2022-01-04T16:28:42+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\\\/\"},\"wordCount\":331,\"image\":{\"@id\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/wp-content\\\/uploads\\\/2016\\\/12\\\/Graphicloads-Filetype-Pdf-150x150.png\",\"articleSection\":[\"Articoli scientifici\",\"Ricerca e Pubblicazioni\"],\"inLanguage\":\"en-GB\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\\\/\",\"url\":\"https:\\\/\\\/www.aica3.org\\\/cms\\\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\\\/\",\"name\":\"Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A - 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Transl. Med. 11, eaat6072 (2019) 27 Novembre 2019 Autore: William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg1, Heather Best1, John Edward Smith, Jochen [&hellip;]","og_url":"https:\/\/www.aica3.org\/cms\/en\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/","og_site_name":"AICa3 - ETS - Associazione Italiana Calpaina 3","article_publisher":"http:\/\/www.facebook.com\/pages\/AICa3-Associazione-Italiana-Calpaina-3\/119599211561350","article_published_time":"2020-02-28T09:02:49+00:00","article_modified_time":"2022-01-04T16:28:42+00:00","og_image":[{"url":"https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf-150x150.png","type":"","width":"","height":""}],"author":"admin","twitter_misc":{"Written by":"admin","Estimated reading time":"2 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.aica3.org\/cms\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/#article","isPartOf":{"@id":"https:\/\/www.aica3.org\/cms\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/"},"author":{"name":"admin","@id":"https:\/\/www.aica3.org\/cms\/#\/schema\/person\/8a5e19b3ab1d1aa2190043f3ddb89aa2"},"headline":"Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A","datePublished":"2020-02-28T09:02:49+00:00","dateModified":"2022-01-04T16:28:42+00:00","mainEntityOfPage":{"@id":"https:\/\/www.aica3.org\/cms\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/"},"wordCount":331,"image":{"@id":"https:\/\/www.aica3.org\/cms\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/#primaryimage"},"thumbnailUrl":"https:\/\/www.aica3.org\/cms\/wp-content\/uploads\/2016\/12\/Graphicloads-Filetype-Pdf-150x150.png","articleSection":["Articoli scientifici","Ricerca e Pubblicazioni"],"inLanguage":"en-GB"},{"@type":"WebPage","@id":"https:\/\/www.aica3.org\/cms\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/","url":"https:\/\/www.aica3.org\/cms\/lo-splicing-della-titina-regola-la-cardiotossicita-associata-alla-terapia-genica-della-calpina-3-per-la-distrofia-muscolare-degli-arti-inferiori-di-tipo-2a\/","name":"Lo splicing della titina regola la cardiotossicit\u00e0 associata alla terapia genica della calpina 3 per la distrofia muscolare degli arti inferiori di tipo 2A - 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