TY  - JOUR
AU  - Venkatesan, Vigneshwaran
AU  - Christopher, Abisha Crystal
AU  - Rhiel, Manuel
AU  - Azhagiri, Manoj Kumar K
AU  - Babu, Prathibha
AU  - Walavalkar, Kaivalya
AU  - Saravanan, Bharath
AU  - Andrieux, Geoffroy
AU  - Rangaraj, Sumathi
AU  - Srinivasan, Saranya
AU  - Karuppusamy, Karthik V
AU  - Jacob, Annlin
AU  - Bagchi, Abhirup
AU  - Pai, Aswin Anand
AU  - Nakamura, Yukio
AU  - Kurita, Ryo
AU  - Balasubramanian, Poonkuzhali
AU  - Pai, Rekha
AU  - Marepally, Srujan Kumar
AU  - Mohankumar, Kumarasamypet Murugesan
AU  - Velayudhan, Shaji R
AU  - Börries, Melanie
AU  - Notani, Dimple
AU  - Cathomen, Toni
AU  - Srivastava, Alok
AU  - Thangavel, Saravanabhavan
TI  - Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies.
JO  - Molecular Therapy / Nucleic Acids
VL  - 32
SN  - 2162-2531
CY  - New York, NY
PB  - Nature Publ. Group
M1  - DKFZ-2023-01028
SP  - 671 - 688
PY  - 2023
AB  - 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.
KW  - HPFH mutation (Other)
KW  - MT: RNA/DNA Editing (Other)
KW  - beta-thalassemia (Other)
KW  - deletional HPFH (Other)
KW  - fetal hemoglobin (Other)
KW  - gene editing (Other)
KW  - gene therapy (Other)
KW  - hematopoietic stem cells (Other)
KW  - large deletions (Other)
KW  - locus control region. (Other)
KW  - sickle cell diseases (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37215154
C2  - pmc:PMC10197010
DO  - DOI:10.1016/j.omtn.2023.04.024
UR  - https://inrepo02.dkfz.de/record/276216
ER  -