دورية أكاديمية
Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34 + cell therapy to induce fetal hemoglobin for sickle cell disease.
| العنوان: | Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34 + cell therapy to induce fetal hemoglobin for sickle cell disease. |
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| المؤلفون: | Katta V; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., O'Keefe K; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Li Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Mayurathan T; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Lazzarotto CR; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Wood RK; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Levine RM; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Powers A; Children's GMP LLC, St. Jude Children's Research Hospital, Memphis, TN, USA., Mayberry K; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Manquen G; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Yao Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang J; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Jang Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Nimmagadda N; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Dempsey EA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Lee G; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Uchida N; Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute / National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health Bethesda, MD, USA., Cheng Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Fazio F; Children's GMP LLC, St. Jude Children's Research Hospital, Memphis, TN, USA., Lockey T; Children's GMP LLC, St. Jude Children's Research Hospital, Memphis, TN, USA., Meagher M; Children's GMP LLC, St. Jude Children's Research Hospital, Memphis, TN, USA., Sharma A; Department of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA., Tisdale JF; Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute / National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health Bethesda, MD, USA., Zhou S; Experimental & Cellular Therapeutics Lab, St. Jude Children's Research Hospital, Memphis, TN, USA., Yen JS; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: shengdar.tsai@stjude.org., Weiss MJ; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: shengdar.tsai@stjude.org., Tsai SQ; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: shengdar.tsai@stjude.org. |
| المصدر: | Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Jul 30. Date of Electronic Publication: 2024 Jul 30. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2017- : Cambridge, MA : Cell Press Original Publication: San Diego, CA : Academic Press, 2000- |
| مستخلص: | Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34 + HSPCs from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies towards clinical trials for treating SCD and other blood disorders. (Copyright © 2024. Published by Elsevier Inc.) |
| تواريخ الأحداث: | Date Created: 20240801 Latest Revision: 20240801 |
| رمز التحديث: | 20240801 |
| DOI: | 10.1016/j.ymthe.2024.07.022 |
| PMID: | 39086133 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1525-0024 |
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| DOI: | 10.1016/j.ymthe.2024.07.022 |