Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease

Frangoul, Haydar; Locatelli, Franco; Bhatia, Monica; Mapara, Markus Y.; Molinari, Lyndsay; Sharma, Akshay; Lobitz, Stephan; Montalembert, Mariane de; Rondelli, Damiano; Steinberg, Martin H.; Walters, Mark C.; Imren, Suzan; Zhang, Lanju; Sharma, A.; Song, Yang; Simard, C; Hobbs, William; Grupp, Stephen

doi:10.1182/blood-2022-162353

Cited by 23 publications

(20 citation statements)

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“…In pre-clinical studies, our approach appears at least comparable in potency and safety to targeting the erythroid-specific enhancer of BCL11A. 13 We observed a small but significant increase in HbF induction targeting the -115 g-globin promoter compared to the BCL11A enhancer target. Zeng et al observed similar increases in their recent study.…”

Section: Discussionmentioning

confidence: 68%

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: Discussionmentioning

confidence: 68%

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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“…Patients receiving exa-cel undergo a myeloablative conditioning regimen, which can lead to significant adverse effects, prior to treatment. Data from patients with severe SCD receiving exa-cel therapy demonstrated that exa-cel therapy resulted in elimination of vaso-occlusive crises in all 95% or more of patients with increases in HbF and total hemoglobin that were maintained throughout the study period [28,29 ▪▪ ]. Adults who received exa-cel therapy reported improvements in their health-related quality of life [30].…”

Section: Text Of Reviewmentioning

confidence: 99%

Systemic medications for sickle cell disease and potential applications for sickle cell retinopathy

Garg,

Scott

2024

Current Opinion in Ophthalmology

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Purpose of review To review the literature evaluating systemic medications for treatment of sickle cell disease (SCD) and their applications for sickle cell retinopathy. Recent Findings Prior studies have demonstrated the efficacy of traditional systemic therapies in reducing the risk of development of sickle cell retinopathy. Since 2017, several new and promising disease-modifying therapies for sickle cell disease have been approved for clinical use, including the first genetic therapies such as exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel). These treatments have shown promising results for systemic management but are not widely utilized due to limited access and high cost. The efficacy of these therapies for the prevention of sickle cell retinopathy remains unknown and opens the door to new avenues for research. Furthermore, the role of systemic therapy for the management of hemoglobin SC (HbSC) disease, which has milder systemic effects but higher likelihood of causing retinopathy, remains poorly understood. Summary Hydroxyurea has been a mainstay of systemic management of SCD with prior work suggesting its ability to reduce the likelihood of developing retinopathy. There are several new and potentially curative systemic therapies for SCD, though their role in retinopathy prevention and management has not been studied extensively. Future studies are necessary to understand the implications of these emerging therapies for sickle cell retinopathy.

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“…Early study results on the first two patients to receive exa-cel reported the editing efficiency of the exa-cel therapeutic to be 68.9% for patient one (received exa-cel for β-thalassemia), and for patient two, there was 82.6 and 78.7% editing efficiency (patient two received two lots of exa-cel for sickle cell disease) [ 92 ]. Subsequent early study results with 31 patients with sickle cell disease reported that after a single exa-cell infusion, all patients in the trial experienced no adverse events related to therapy and no vaso-occlusive crises for 2–32 months after exa-cell therapy (for reference, patients experienced 2–9.5 severe vaso-occlusive crises in the two years preceding exa-cel) [ 93 ]; at six months post infusion, the average percentage of bone marrow CD34 + HSPCs or peripheral blood mononuclear cells (PBMCs) with an edited BCL11A allele was 86.6% or 76.0%, respectively. Additionally, early results from a β-thalassemia trial indicated that out of the 44 individuals in the trial, 42 of them did not require RBC transfusion post therapy in the 1–36 months post exa-cel; the 2 patients that had not stopped RBC transfusion had reduced the transfusion volume by ~80% (for reference, these 44 individuals had received between 15 and 71 RBC transfusions in the two years preceding exa-cell therapy) [ 94 ]; editing efficiencies were somewhat reduced in this study compared to the aforementioned trial for sickle cell disease, with the average percentage of bone marrow CD34 + HSPCs or PBMCs containing an edited BCL11A allele was 74.3% or 63.4%, respectively…”

Section: Current Use Of Crispr-cas Systems In Clinical Trialsmentioning

confidence: 99%

CRISPR-Cas System: The Current and Emerging Translational Landscape

Bhokisham

Laudermilch

Traeger

et al. 2023

Cells

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CRISPR-Cas technology has rapidly changed life science research and human medicine. The ability to add, remove, or edit human DNA sequences has transformative potential for treating congenital and acquired human diseases. The timely maturation of the cell and gene therapy ecosystem and its seamless integration with CRISPR-Cas technologies has enabled the development of therapies that could potentially cure not only monogenic diseases such as sickle cell anemia and muscular dystrophy, but also complex heterogenous diseases such as cancer and diabetes. Here, we review the current landscape of clinical trials involving the use of various CRISPR-Cas systems as therapeutics for human diseases, discuss challenges, and explore new CRISPR-Cas-based tools such as base editing, prime editing, CRISPR-based transcriptional regulation, CRISPR-based epigenome editing, and RNA editing, each promising new functionality and broadening therapeutic potential. Finally, we discuss how the CRISPR-Cas system is being used to understand the biology of human diseases through the generation of large animal disease models used for preclinical testing of emerging therapeutics.

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Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease

Cited by 23 publications

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

Systemic medications for sickle cell disease and potential applications for sickle cell retinopathy

CRISPR-Cas System: The Current and Emerging Translational Landscape

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Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease

Cited by 23 publications

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

Systemic medications for sickle cell disease and potential applications for sickle cell retinopathy

CRISPR-Cas System: The Current and Emerging Translational Landscape

Contact Info

Product

Resources

About

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