Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47 phox -Deficient Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with...
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Veröffentlicht in: | Human gene therapy 2021-09, Vol.32 (17-18), p.949-958 |
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container_title | Human gene therapy |
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creator | Schejtman, Andrea Vetharoy, Winston Choi, Uimook Rivat, Christine Theobald, Narda Piras, Giuseppa Leon-Rico, Diego Buckland, Karen Armenteros-Monterroso, Elena Benedetti, Sara Ashworth, Michael T Rothe, Michael Schambach, Axel Gaspar, Hubert Bobby Kang, Elizabeth M Malech, Harry L Thrasher, Adrian J Santilli, Giorgia |
description | Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47
-deficient CGD (p47
CGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34
cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34
cells derived from a p47
CGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47
CGD. |
doi_str_mv | 10.1089/hum.2020.276 |
format | Article |
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-deficient CGD (p47
CGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34
cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34
cells derived from a p47
CGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47
CGD.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2020.276</identifier><identifier>PMID: 33740872</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Genetic Therapy ; Granulomatous Disease, Chronic - genetics ; Granulomatous Disease, Chronic - therapy ; Humans ; Mice ; NADPH Oxidases - genetics ; NADPH Oxidases - metabolism ; Tissue Distribution</subject><ispartof>Human gene therapy, 2021-09, Vol.32 (17-18), p.949-958</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1032-344eb74d6462900fe1f2554496e0a417a03298365f498c7866e2d8ce2661217a3</citedby><cites>FETCH-LOGICAL-c1032-344eb74d6462900fe1f2554496e0a417a03298365f498c7866e2d8ce2661217a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33740872$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schejtman, Andrea</creatorcontrib><creatorcontrib>Vetharoy, Winston</creatorcontrib><creatorcontrib>Choi, Uimook</creatorcontrib><creatorcontrib>Rivat, Christine</creatorcontrib><creatorcontrib>Theobald, Narda</creatorcontrib><creatorcontrib>Piras, Giuseppa</creatorcontrib><creatorcontrib>Leon-Rico, Diego</creatorcontrib><creatorcontrib>Buckland, Karen</creatorcontrib><creatorcontrib>Armenteros-Monterroso, Elena</creatorcontrib><creatorcontrib>Benedetti, Sara</creatorcontrib><creatorcontrib>Ashworth, Michael T</creatorcontrib><creatorcontrib>Rothe, Michael</creatorcontrib><creatorcontrib>Schambach, Axel</creatorcontrib><creatorcontrib>Gaspar, Hubert Bobby</creatorcontrib><creatorcontrib>Kang, Elizabeth M</creatorcontrib><creatorcontrib>Malech, Harry L</creatorcontrib><creatorcontrib>Thrasher, Adrian J</creatorcontrib><creatorcontrib>Santilli, Giorgia</creatorcontrib><title>Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47 phox -Deficient Chronic Granulomatous Disease</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47
-deficient CGD (p47
CGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34
cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34
cells derived from a p47
CGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47
CGD.</description><subject>Animals</subject><subject>Genetic Therapy</subject><subject>Granulomatous Disease, Chronic - genetics</subject><subject>Granulomatous Disease, Chronic - therapy</subject><subject>Humans</subject><subject>Mice</subject><subject>NADPH Oxidases - genetics</subject><subject>NADPH Oxidases - metabolism</subject><subject>Tissue Distribution</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF1LwzAUhoMoTqd3Xkt-gJ35atJeyqZTGE7YvC5Ze0Ija1OSVp2X_nIzpl6dA-c57wsPQleUTCjJ8tt6aCaMMDJhSh6hM5qmKlGCseO4E8ETwgUbofMQ3gihPJXqFI04V4Jkip2h7xcP5da2ttRbvOx629gv3VvXYt1WeKUN9Du86ofKQsDOYI2f4QMvoO3tu_XxZw4t4HUNXnc7bJzHnVC4q90nTmZgbGkjiqe1d7ECz71uh61rdO-GgGc2gA5wgU6M3ga4_J1j9Ppwv54-Jovl_Gl6t0hKSjhLuBCwUaKSQrKcEAPUsDQVIpdAtKBKRyjPuEyNyLNSZVICq7ISmJSUxTMfo5tDbuldCB5M0XnbaL8rKCn2KouostirLKLKiF8f8G7YNFD9w3_u-A_kBW8Y</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Schejtman, Andrea</creator><creator>Vetharoy, Winston</creator><creator>Choi, Uimook</creator><creator>Rivat, Christine</creator><creator>Theobald, Narda</creator><creator>Piras, Giuseppa</creator><creator>Leon-Rico, Diego</creator><creator>Buckland, Karen</creator><creator>Armenteros-Monterroso, Elena</creator><creator>Benedetti, Sara</creator><creator>Ashworth, Michael T</creator><creator>Rothe, Michael</creator><creator>Schambach, Axel</creator><creator>Gaspar, Hubert Bobby</creator><creator>Kang, Elizabeth M</creator><creator>Malech, Harry L</creator><creator>Thrasher, Adrian J</creator><creator>Santilli, Giorgia</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>202109</creationdate><title>Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47 phox -Deficient Chronic Granulomatous Disease</title><author>Schejtman, Andrea ; Vetharoy, Winston ; Choi, Uimook ; Rivat, Christine ; Theobald, Narda ; Piras, Giuseppa ; Leon-Rico, Diego ; Buckland, Karen ; Armenteros-Monterroso, Elena ; Benedetti, Sara ; Ashworth, Michael T ; Rothe, Michael ; Schambach, Axel ; Gaspar, Hubert Bobby ; Kang, Elizabeth M ; Malech, Harry L ; Thrasher, Adrian J ; Santilli, Giorgia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1032-344eb74d6462900fe1f2554496e0a417a03298365f498c7866e2d8ce2661217a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Genetic Therapy</topic><topic>Granulomatous Disease, Chronic - genetics</topic><topic>Granulomatous Disease, Chronic - therapy</topic><topic>Humans</topic><topic>Mice</topic><topic>NADPH Oxidases - genetics</topic><topic>NADPH Oxidases - metabolism</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schejtman, Andrea</creatorcontrib><creatorcontrib>Vetharoy, Winston</creatorcontrib><creatorcontrib>Choi, Uimook</creatorcontrib><creatorcontrib>Rivat, Christine</creatorcontrib><creatorcontrib>Theobald, Narda</creatorcontrib><creatorcontrib>Piras, Giuseppa</creatorcontrib><creatorcontrib>Leon-Rico, Diego</creatorcontrib><creatorcontrib>Buckland, Karen</creatorcontrib><creatorcontrib>Armenteros-Monterroso, Elena</creatorcontrib><creatorcontrib>Benedetti, Sara</creatorcontrib><creatorcontrib>Ashworth, Michael T</creatorcontrib><creatorcontrib>Rothe, Michael</creatorcontrib><creatorcontrib>Schambach, Axel</creatorcontrib><creatorcontrib>Gaspar, Hubert Bobby</creatorcontrib><creatorcontrib>Kang, Elizabeth M</creatorcontrib><creatorcontrib>Malech, Harry L</creatorcontrib><creatorcontrib>Thrasher, Adrian J</creatorcontrib><creatorcontrib>Santilli, Giorgia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schejtman, Andrea</au><au>Vetharoy, Winston</au><au>Choi, Uimook</au><au>Rivat, Christine</au><au>Theobald, Narda</au><au>Piras, Giuseppa</au><au>Leon-Rico, Diego</au><au>Buckland, Karen</au><au>Armenteros-Monterroso, Elena</au><au>Benedetti, Sara</au><au>Ashworth, Michael T</au><au>Rothe, Michael</au><au>Schambach, Axel</au><au>Gaspar, Hubert Bobby</au><au>Kang, Elizabeth M</au><au>Malech, Harry L</au><au>Thrasher, Adrian J</au><au>Santilli, Giorgia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47 phox -Deficient Chronic Granulomatous Disease</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2021-09</date><risdate>2021</risdate><volume>32</volume><issue>17-18</issue><spage>949</spage><epage>958</epage><pages>949-958</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><abstract>Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47
-deficient CGD (p47
CGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34
cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34
cells derived from a p47
CGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47
CGD.</abstract><cop>United States</cop><pmid>33740872</pmid><doi>10.1089/hum.2020.276</doi><tpages>10</tpages></addata></record> |
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subjects | Animals Genetic Therapy Granulomatous Disease, Chronic - genetics Granulomatous Disease, Chronic - therapy Humans Mice NADPH Oxidases - genetics NADPH Oxidases - metabolism Tissue Distribution |
title | Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47 phox -Deficient Chronic Granulomatous Disease |
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