BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate
Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs)...
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| creator | Demirci, Selami Zeng, Jing Palchaudhuri, Rahul Wu, Chuanfeng Abraham, Diana M Hayal, Taha B Essawi, Khaled Nguyen, My Anh Stasula, Ulana Chu, Rebecca Leonard, Alexis Porter, Shaina N Khan, Muhammad Behroz Naeem Hinojosa, Gabriela Uchida, Naoya Hong, Sogun Lazzarotto, Cicera R Neri, Nola R da Silva, Lucas Ferreira Pellin, Danilo Verma, Archana Lanieri, Leanne Bhat, Anjali Hammond, Katelyn Tate, Tiffany Maitland, Stacy A Sheikhsaran, Fatemeh Bonifacino, Aylin C Krouse, Allen E Linde, Nathaniel S Engels, Theresa Golomb, Justin Tsai, Shengdar Q Pruett-Miller, Shondra M Scadden, David T Dunbar, Cynthia E Wolfe, Scot A Donahue, Robert E Olson, Lisa M Bauer, Daniel E Tisdale, John F |
| description | Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations. HbF levels were further boosted by stress erythropoiesis or hydroxyurea. Bone marrow analysis revealed that gene edits were predominantly programmed deletions, programmed inversions, and short indels, each disrupting the enhancer core TGN
WGATAR half E-box/GATA binding motifs. Nonprogrammed long deletions were disfavored in engrafting cells. CD45 antibody-drug conjugate (ADC) conditioning achieved comparable engraftment and HbF reactivation, whereas lentiviral vector tracking showed polyclonal reconstitution with dynamics similar to animals conditioned with total body irradiation (TBI) or busulfan. Joining CD45-ADC conditioning with combined enhancer editing presents an effective strategy for β-hemoglobinopathies, enabling durable HbF reactivation without chemotherapy. |
| doi_str_mv | 10.1016/j.stem.2024.10.014 |
| format | Article |
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WGATAR half E-box/GATA binding motifs. Nonprogrammed long deletions were disfavored in engrafting cells. CD45 antibody-drug conjugate (ADC) conditioning achieved comparable engraftment and HbF reactivation, whereas lentiviral vector tracking showed polyclonal reconstitution with dynamics similar to animals conditioned with total body irradiation (TBI) or busulfan. Joining CD45-ADC conditioning with combined enhancer editing presents an effective strategy for β-hemoglobinopathies, enabling durable HbF reactivation without chemotherapy.</description><identifier>ISSN: 1934-5909</identifier><identifier>ISSN: 1875-9777</identifier><identifier>EISSN: 1875-9777</identifier><identifier>DOI: 10.1016/j.stem.2024.10.014</identifier><identifier>PMID: 39642886</identifier><language>eng</language><publisher>United States</publisher><ispartof>Cell stem cell, 2024-12</ispartof><rights>Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c996-96f792de8492fcf37a1040204db3cb95c9a9bce23dcc6da380d7f609dada29ff3</cites><orcidid>0000-0002-6174-1609</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39642886$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Demirci, Selami</creatorcontrib><creatorcontrib>Zeng, Jing</creatorcontrib><creatorcontrib>Palchaudhuri, Rahul</creatorcontrib><creatorcontrib>Wu, Chuanfeng</creatorcontrib><creatorcontrib>Abraham, Diana M</creatorcontrib><creatorcontrib>Hayal, Taha B</creatorcontrib><creatorcontrib>Essawi, Khaled</creatorcontrib><creatorcontrib>Nguyen, My Anh</creatorcontrib><creatorcontrib>Stasula, Ulana</creatorcontrib><creatorcontrib>Chu, Rebecca</creatorcontrib><creatorcontrib>Leonard, Alexis</creatorcontrib><creatorcontrib>Porter, Shaina N</creatorcontrib><creatorcontrib>Khan, Muhammad Behroz Naeem</creatorcontrib><creatorcontrib>Hinojosa, Gabriela</creatorcontrib><creatorcontrib>Uchida, Naoya</creatorcontrib><creatorcontrib>Hong, Sogun</creatorcontrib><creatorcontrib>Lazzarotto, Cicera R</creatorcontrib><creatorcontrib>Neri, Nola R</creatorcontrib><creatorcontrib>da Silva, Lucas Ferreira</creatorcontrib><creatorcontrib>Pellin, Danilo</creatorcontrib><creatorcontrib>Verma, Archana</creatorcontrib><creatorcontrib>Lanieri, Leanne</creatorcontrib><creatorcontrib>Bhat, Anjali</creatorcontrib><creatorcontrib>Hammond, Katelyn</creatorcontrib><creatorcontrib>Tate, Tiffany</creatorcontrib><creatorcontrib>Maitland, Stacy A</creatorcontrib><creatorcontrib>Sheikhsaran, Fatemeh</creatorcontrib><creatorcontrib>Bonifacino, Aylin C</creatorcontrib><creatorcontrib>Krouse, Allen E</creatorcontrib><creatorcontrib>Linde, Nathaniel S</creatorcontrib><creatorcontrib>Engels, Theresa</creatorcontrib><creatorcontrib>Golomb, Justin</creatorcontrib><creatorcontrib>Tsai, Shengdar Q</creatorcontrib><creatorcontrib>Pruett-Miller, Shondra M</creatorcontrib><creatorcontrib>Scadden, David T</creatorcontrib><creatorcontrib>Dunbar, Cynthia E</creatorcontrib><creatorcontrib>Wolfe, Scot A</creatorcontrib><creatorcontrib>Donahue, Robert E</creatorcontrib><creatorcontrib>Olson, Lisa M</creatorcontrib><creatorcontrib>Bauer, Daniel E</creatorcontrib><creatorcontrib>Tisdale, John F</creatorcontrib><title>BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate</title><title>Cell stem cell</title><addtitle>Cell Stem Cell</addtitle><description>Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations. HbF levels were further boosted by stress erythropoiesis or hydroxyurea. Bone marrow analysis revealed that gene edits were predominantly programmed deletions, programmed inversions, and short indels, each disrupting the enhancer core TGN
WGATAR half E-box/GATA binding motifs. Nonprogrammed long deletions were disfavored in engrafting cells. CD45 antibody-drug conjugate (ADC) conditioning achieved comparable engraftment and HbF reactivation, whereas lentiviral vector tracking showed polyclonal reconstitution with dynamics similar to animals conditioned with total body irradiation (TBI) or busulfan. 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Zeng, Jing ; Palchaudhuri, Rahul ; Wu, Chuanfeng ; Abraham, Diana M ; Hayal, Taha B ; Essawi, Khaled ; Nguyen, My Anh ; Stasula, Ulana ; Chu, Rebecca ; Leonard, Alexis ; Porter, Shaina N ; Khan, Muhammad Behroz Naeem ; Hinojosa, Gabriela ; Uchida, Naoya ; Hong, Sogun ; Lazzarotto, Cicera R ; Neri, Nola R ; da Silva, Lucas Ferreira ; Pellin, Danilo ; Verma, Archana ; Lanieri, Leanne ; Bhat, Anjali ; Hammond, Katelyn ; Tate, Tiffany ; Maitland, Stacy A ; Sheikhsaran, Fatemeh ; Bonifacino, Aylin C ; Krouse, Allen E ; Linde, Nathaniel S ; Engels, Theresa ; Golomb, Justin ; Tsai, Shengdar Q ; Pruett-Miller, Shondra M ; Scadden, David T ; Dunbar, Cynthia E ; Wolfe, Scot A ; Donahue, Robert E ; Olson, Lisa M ; Bauer, Daniel E ; Tisdale, John F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c996-96f792de8492fcf37a1040204db3cb95c9a9bce23dcc6da380d7f609dada29ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Demirci, Selami</creatorcontrib><creatorcontrib>Zeng, Jing</creatorcontrib><creatorcontrib>Palchaudhuri, Rahul</creatorcontrib><creatorcontrib>Wu, Chuanfeng</creatorcontrib><creatorcontrib>Abraham, Diana M</creatorcontrib><creatorcontrib>Hayal, Taha B</creatorcontrib><creatorcontrib>Essawi, Khaled</creatorcontrib><creatorcontrib>Nguyen, My Anh</creatorcontrib><creatorcontrib>Stasula, Ulana</creatorcontrib><creatorcontrib>Chu, Rebecca</creatorcontrib><creatorcontrib>Leonard, Alexis</creatorcontrib><creatorcontrib>Porter, Shaina N</creatorcontrib><creatorcontrib>Khan, Muhammad Behroz Naeem</creatorcontrib><creatorcontrib>Hinojosa, Gabriela</creatorcontrib><creatorcontrib>Uchida, Naoya</creatorcontrib><creatorcontrib>Hong, Sogun</creatorcontrib><creatorcontrib>Lazzarotto, Cicera R</creatorcontrib><creatorcontrib>Neri, Nola R</creatorcontrib><creatorcontrib>da Silva, Lucas Ferreira</creatorcontrib><creatorcontrib>Pellin, Danilo</creatorcontrib><creatorcontrib>Verma, Archana</creatorcontrib><creatorcontrib>Lanieri, Leanne</creatorcontrib><creatorcontrib>Bhat, Anjali</creatorcontrib><creatorcontrib>Hammond, Katelyn</creatorcontrib><creatorcontrib>Tate, Tiffany</creatorcontrib><creatorcontrib>Maitland, Stacy A</creatorcontrib><creatorcontrib>Sheikhsaran, Fatemeh</creatorcontrib><creatorcontrib>Bonifacino, Aylin C</creatorcontrib><creatorcontrib>Krouse, Allen E</creatorcontrib><creatorcontrib>Linde, Nathaniel S</creatorcontrib><creatorcontrib>Engels, Theresa</creatorcontrib><creatorcontrib>Golomb, Justin</creatorcontrib><creatorcontrib>Tsai, Shengdar Q</creatorcontrib><creatorcontrib>Pruett-Miller, Shondra M</creatorcontrib><creatorcontrib>Scadden, David T</creatorcontrib><creatorcontrib>Dunbar, Cynthia E</creatorcontrib><creatorcontrib>Wolfe, Scot A</creatorcontrib><creatorcontrib>Donahue, Robert E</creatorcontrib><creatorcontrib>Olson, Lisa M</creatorcontrib><creatorcontrib>Bauer, Daniel E</creatorcontrib><creatorcontrib>Tisdale, John F</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell stem cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Demirci, Selami</au><au>Zeng, Jing</au><au>Palchaudhuri, Rahul</au><au>Wu, Chuanfeng</au><au>Abraham, Diana M</au><au>Hayal, Taha B</au><au>Essawi, Khaled</au><au>Nguyen, My Anh</au><au>Stasula, Ulana</au><au>Chu, Rebecca</au><au>Leonard, Alexis</au><au>Porter, Shaina N</au><au>Khan, Muhammad Behroz Naeem</au><au>Hinojosa, Gabriela</au><au>Uchida, Naoya</au><au>Hong, Sogun</au><au>Lazzarotto, Cicera R</au><au>Neri, Nola R</au><au>da Silva, Lucas Ferreira</au><au>Pellin, Danilo</au><au>Verma, Archana</au><au>Lanieri, Leanne</au><au>Bhat, Anjali</au><au>Hammond, Katelyn</au><au>Tate, Tiffany</au><au>Maitland, Stacy A</au><au>Sheikhsaran, Fatemeh</au><au>Bonifacino, Aylin C</au><au>Krouse, Allen E</au><au>Linde, Nathaniel S</au><au>Engels, Theresa</au><au>Golomb, Justin</au><au>Tsai, Shengdar Q</au><au>Pruett-Miller, Shondra M</au><au>Scadden, David T</au><au>Dunbar, Cynthia E</au><au>Wolfe, Scot A</au><au>Donahue, Robert E</au><au>Olson, Lisa M</au><au>Bauer, Daniel E</au><au>Tisdale, John F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate</atitle><jtitle>Cell stem cell</jtitle><addtitle>Cell Stem Cell</addtitle><date>2024-12-05</date><risdate>2024</risdate><issn>1934-5909</issn><issn>1875-9777</issn><eissn>1875-9777</eissn><abstract>Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations. HbF levels were further boosted by stress erythropoiesis or hydroxyurea. Bone marrow analysis revealed that gene edits were predominantly programmed deletions, programmed inversions, and short indels, each disrupting the enhancer core TGN
WGATAR half E-box/GATA binding motifs. Nonprogrammed long deletions were disfavored in engrafting cells. CD45 antibody-drug conjugate (ADC) conditioning achieved comparable engraftment and HbF reactivation, whereas lentiviral vector tracking showed polyclonal reconstitution with dynamics similar to animals conditioned with total body irradiation (TBI) or busulfan. Joining CD45-ADC conditioning with combined enhancer editing presents an effective strategy for β-hemoglobinopathies, enabling durable HbF reactivation without chemotherapy.</abstract><cop>United States</cop><pmid>39642886</pmid><doi>10.1016/j.stem.2024.10.014</doi><orcidid>https://orcid.org/0000-0002-6174-1609</orcidid></addata></record> |
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| title | BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate |
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