دورية أكاديمية
Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy
| العنوان: | Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy |
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| المؤلفون: | Christian Brendel, Olivier Negre, Michael Rothe, Swaroopa Guda, Geoff Parsons, Chad Harris, Meaghan McGuinness, Daniela Abriss, Alla Tsytsykova, Denise Klatt, Martin Bentler, Danilo Pellin, Lauryn Christiansen, Axel Schambach, John Manis, Helene Trebeden-Negre, Melissa Bonner, Erica Esrick, Gabor Veres, Myriam Armant, David A. Williams |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 17, Iss , Pp 589-600 (2020) |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| المجموعة: | LCC:Genetics LCC:Cytology |
| مصطلحات موضوعية: | Sickle cell disease, HbS, hemoglobinopathies, gene therapy, lentiviral vector, BCL11A, Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | In this work we provide preclinical data to support initiation of a first-in-human trial for sickle cell disease (SCD) using an approach that relies on reversal of the developmental fetal-to-adult hemoglobin switch. Erythroid-specific knockdown of BCL11A via a lentiviral-encoded microRNA-adapted short hairpin RNA (shRNAmiR) leads to reactivation of the gamma-globin gene while simultaneously reducing expression of the pathogenic adult sickle β-globin. We generated a refined lentiviral vector (LVV) BCH-BB694 that was developed to overcome poor vector titers observed in the manufacturing scale-up of the original research-grade LVV. Healthy or sickle cell donor CD34+ cells transduced with Good Manufacturing Practices (GMP)-grade BCH-BB694 LVV achieved high vector copy numbers (VCNs) >5 and gene marking of >80%, resulting in a 3- to 5-fold induction of fetal hemoglobin (HbF) compared with mock-transduced cells without affecting growth, differentiation, and engraftment of gene-modified cells in vitro or in vivo. In vitro immortalization assays, which are designed to measure vector-mediated genotoxicity, showed no increased immortalization compared with mock-transduced cells. Together these data demonstrate that BCH-BB694 LVV is non-toxic and efficacious in preclinical studies, and can be generated at a clinically relevant scale in a GMP setting at high titer to support clinical testing for the treatment of SCD. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2329-0501 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2329050120300450; https://doaj.org/toc/2329-0501 |
| DOI: | 10.1016/j.omtm.2020.03.015 |
| URL الوصول: | https://doaj.org/article/7ebf28bc3d664f328d3cea76508fe211 |
| رقم الأكسشن: | edsdoj.7ebf28bc3d664f328d3cea76508fe211 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2020.03.015 |