Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies
Reactivation of fetal hemoglobin (HbF) is a commonly adapted strategy to ameliorate β-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits HbF tetramer production affecting the therapeutic benefits. Here, we evaluated deletional hereditary persistence of f...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123001105 |
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| author | Vigneshwaran Venkatesan Abisha Crystal Christopher Manuel Rhiel Manoj Kumar K. Azhagiri Prathibha Babu Kaivalya Walavalkar Bharath Saravanan Geoffroy Andrieux Sumathi Rangaraj Saranya Srinivasan Karthik V. Karuppusamy Annlin Jacob Abhirup Bagchi Aswin Anand Pai Yukio Nakamura Ryo Kurita Poonkuzhali Balasubramanian Rekha Pai Srujan Kumar Marepally Kumarasamypet Murugesan Mohankumar Shaji R. Velayudhan Melanie Boerries Dimple Notani Toni Cathomen Alok Srivastava Saravanabhavan Thangavel |
| author_facet | Vigneshwaran Venkatesan Abisha Crystal Christopher Manuel Rhiel Manoj Kumar K. Azhagiri Prathibha Babu Kaivalya Walavalkar Bharath Saravanan Geoffroy Andrieux Sumathi Rangaraj Saranya Srinivasan Karthik V. Karuppusamy Annlin Jacob Abhirup Bagchi Aswin Anand Pai Yukio Nakamura Ryo Kurita Poonkuzhali Balasubramanian Rekha Pai Srujan Kumar Marepally Kumarasamypet Murugesan Mohankumar Shaji R. Velayudhan Melanie Boerries Dimple Notani Toni Cathomen Alok Srivastava Saravanabhavan Thangavel |
| author_sort | Vigneshwaran Venkatesan |
| collection | DOAJ |
| description | Reactivation of fetal hemoglobin (HbF) is a commonly adapted strategy to ameliorate β-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits HbF tetramer production affecting the therapeutic benefits. Here, we evaluated deletional hereditary persistence of fetal hemoglobin (HPFH) mutations and identified an 11-kb sequence, encompassing putative repressor region (PRR) to β-globin exon-1 (βE1), as the core deletion that ablates HbA and exhibits superior HbF production compared with HPFH or other well-established targets. PRR-βE1-edited hematopoietic stem and progenitor cells (HSPCs) retained their genome integrity and their engraftment potential to repopulate for long-term hematopoiesis in immunocompromised mice producing HbF positive cells in vivo. Furthermore, PRR-βE1 gene editing is feasible without ex vivo HSPC culture. Importantly, the editing induced therapeutically significant levels of HbF to reverse the phenotypes of both sickle cell disease and β-thalassemia major. These findings imply that PRR-βE1 gene editing of patient HSPCs could lead to improved therapeutic outcomes for β-hemoglobinopathy gene therapy. |
| first_indexed | 2024-04-09T12:39:36Z |
| format | Article |
| id | doaj.art-444686798a7c40d7a355be2ff089b162 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-09T12:39:36Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-444686798a7c40d7a355be2ff089b1622023-05-15T04:14:40ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-06-0132671688Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathiesVigneshwaran Venkatesan0Abisha Crystal Christopher1Manuel Rhiel2Manoj Kumar K. Azhagiri3Prathibha Babu4Kaivalya Walavalkar5Bharath Saravanan6Geoffroy Andrieux7Sumathi Rangaraj8Saranya Srinivasan9Karthik V. Karuppusamy10Annlin Jacob11Abhirup Bagchi12Aswin Anand Pai13Yukio Nakamura14Ryo Kurita15Poonkuzhali Balasubramanian16Rekha Pai17Srujan Kumar Marepally18Kumarasamypet Murugesan Mohankumar19Shaji R. Velayudhan20Melanie Boerries21Dimple Notani22Toni Cathomen23Alok Srivastava24Saravanabhavan Thangavel25Centre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Manipal Academy of Higher Education, Manipal 576104, Karnataka, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaInstitute for Transfusion Medicine and Gene Therapy, Medical Center – University of Freiburg, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Faculty, University of Freiburg, 79106 Freiburg, GermanyCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Manipal Academy of Higher Education, Manipal 576104, Karnataka, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Manipal Academy of Higher Education, Manipal 576104, Karnataka, IndiaNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, Karnataka 560065, IndiaNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, Karnataka 560065, IndiaInstitute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine & Medical Center - University of Freiburg, 79106 Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Manipal Academy of Higher Education, Manipal 576104, Karnataka, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaDepartment of Hematology, Christian Medical College, Vellore, Tamil Nadu 632004, IndiaCell Engineering Division, RIKEN BioResource Research Center, Ibaraki 3050074, JapanCell Engineering Division, RIKEN BioResource Research Center, Ibaraki 3050074, JapanDepartment of Hematology, Christian Medical College, Vellore, Tamil Nadu 632004, IndiaDepartment of Pathology, Christian Medical College, Vellore, Tamil Nadu 632004, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Department of Hematology, Christian Medical College, Vellore, Tamil Nadu 632004, IndiaInstitute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine & Medical Center - University of Freiburg, 79106 Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, Karnataka 560065, IndiaInstitute for Transfusion Medicine and Gene Therapy, Medical Center – University of Freiburg, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Faculty, University of Freiburg, 79106 Freiburg, GermanyCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Department of Hematology, Christian Medical College, Vellore, Tamil Nadu 632004, IndiaCentre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India; Corresponding author: Saravanabhavan Thangavel, Centre for Stem Cell Research (CSCR), A Unit of InStem Bengaluru, Christian Medical College Campus, Vellore, Tamil Nadu 632002, India.Reactivation of fetal hemoglobin (HbF) is a commonly adapted strategy to ameliorate β-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits HbF tetramer production affecting the therapeutic benefits. Here, we evaluated deletional hereditary persistence of fetal hemoglobin (HPFH) mutations and identified an 11-kb sequence, encompassing putative repressor region (PRR) to β-globin exon-1 (βE1), as the core deletion that ablates HbA and exhibits superior HbF production compared with HPFH or other well-established targets. PRR-βE1-edited hematopoietic stem and progenitor cells (HSPCs) retained their genome integrity and their engraftment potential to repopulate for long-term hematopoiesis in immunocompromised mice producing HbF positive cells in vivo. Furthermore, PRR-βE1 gene editing is feasible without ex vivo HSPC culture. Importantly, the editing induced therapeutically significant levels of HbF to reverse the phenotypes of both sickle cell disease and β-thalassemia major. These findings imply that PRR-βE1 gene editing of patient HSPCs could lead to improved therapeutic outcomes for β-hemoglobinopathy gene therapy.http://www.sciencedirect.com/science/article/pii/S2162253123001105MT: RNA/DNA Editingdeletional HPFHsickle cell diseasesbeta-thalassemiagene editinggene therapy |
| spellingShingle | Vigneshwaran Venkatesan Abisha Crystal Christopher Manuel Rhiel Manoj Kumar K. Azhagiri Prathibha Babu Kaivalya Walavalkar Bharath Saravanan Geoffroy Andrieux Sumathi Rangaraj Saranya Srinivasan Karthik V. Karuppusamy Annlin Jacob Abhirup Bagchi Aswin Anand Pai Yukio Nakamura Ryo Kurita Poonkuzhali Balasubramanian Rekha Pai Srujan Kumar Marepally Kumarasamypet Murugesan Mohankumar Shaji R. Velayudhan Melanie Boerries Dimple Notani Toni Cathomen Alok Srivastava Saravanabhavan Thangavel Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies Molecular Therapy: Nucleic Acids MT: RNA/DNA Editing deletional HPFH sickle cell diseases beta-thalassemia gene editing gene therapy |
| title | Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies |
| title_full | Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies |
| title_fullStr | Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies |
| title_full_unstemmed | Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies |
| title_short | Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies |
| title_sort | editing the core region in hpfh deletions alters fetal and adult globin expression for treatment of β hemoglobinopathies |
| topic | MT: RNA/DNA Editing deletional HPFH sickle cell diseases beta-thalassemia gene editing gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123001105 |
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