Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β-Thalassemia (TDT) or Sickle Cell Disease (SCD): Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-Cas9-Modified CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs)

Frangoul, Haydar; Soni, Sandeep; Bobruff, Yael; Cappellini, Maria Domenica; Corbacioglu, Selim; Fernandez, Christine; Fuente, Josu de la; Grupp, Stephan A.; Handgretinger, Rupert; Ho, Tony W.; Imren, Suzan; Kattamis, Antonis; Lekstrom-Himes, Julie; Locatelli, Franco; Lu, Yun; Mapara, Markus Y.; Mulcahey, Sarah D.; Montalembert, Mariane de; Rondelli, Damiano; Shanbhag, Niraj M.; Sheth, Sujit; Steinberg, Martin H.; Weinstein, M.C.; Wu, John; Wall, Donna A.

doi:10.1016/s2666-6367(21)00101-9

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“…27,30 A clinical trial examining Cas9-mediated disruption of the BCL11A enhancer shows promising early results in patients with SCD or bthalassemia. 10,31,32 Previously, we showed that Cas9 disruption of a BCL11A repressor-binding site (113 to 118 nucleotides upstream of the transcription start site in the g-globin gene promoters) in HSCs resulted in the induction of HbF to potentially therapeutic levels in RBC progeny generated in in vitro and in vivo. 27,33 Potential advantages of our approach include transient Cas9 expression for ex vivo modification of autologous HSCs and high efficiency of NHEJ-mediated g-globin promoter editing compared to HDR correction of the HbS mutation.…”

Section: Introductionmentioning

confidence: 99%

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Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34⁺cell therapy to induce fetal hemoglobin for sickle cell disease

Katta,

O’Keefe,

et al. 2024

Preprint

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Sickle cell disease (SCD) is a common severe blood disorder, caused by one major point mutation in the HBB gene. Current pharmacotherapies are only partially effective and potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of autologous patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers a potentially curative approach to treat SCD and circumvents some problems associated with allogeneic HSCT. Although the FDA has released guidelines for evaluating genome editing risks, it remains unclear how to best to assess the preclinical safety and efficacy of genome-edited cellular drug products to prepare for a clinical trial. Here we describe rigorous pre-clinical characterization and optimization of a therapeutic gamma-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared targets in the gamma-globin promoter and BCL11A erythroid-specific enhancer, identified a lead candidate that potently induces HbF, and tested our approach in mobilized CD34+ HSPCs from normal donors and individuals with SCD. We observed efficient editing, induction of HbF to levels predicted to be therapeutic, and reduction of sickling in red blood cells derived from edited HSPCs. With single-cell western and RNA-seq analyses, we defined the heterogeneity and specificity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased genome-wide off-target discovery followed by multiplexed targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new discoveries on ex vivo genome editing of HSCs towards clinical trials for treating SCD and other blood disorders.

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Section: Introductionmentioning

confidence: 99%

“…27,30 A clinical trial examining Cas9-mediated disruption of the BCL11A enhancer shows promising early results in patients with SCD or β-thalassemia. 10,31,32…”

Section: Introductionmentioning

confidence: 99%

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34⁺cell therapy to induce fetal hemoglobin for sickle cell disease

Katta,

O’Keefe,

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β-Thalassemia (TDT) or Sickle Cell Disease (SCD): Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-Cas9-Modified CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs)

Cited by 1 publication

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Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34⁺cell therapy to induce fetal hemoglobin for sickle cell disease

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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Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β-Thalassemia (TDT) or Sickle Cell Disease (SCD): Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-Cas9-Modified CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs)

Cited by 1 publication

References 0 publications

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+cell therapy to induce fetal hemoglobin for sickle cell disease

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+cell therapy to induce fetal hemoglobin for sickle cell disease

Contact Info

Product

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Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34⁺cell therapy to induce fetal hemoglobin for sickle cell disease

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34⁺cell therapy to induce fetal hemoglobin for sickle cell disease