Casgevy (exagamglogene autotemcel) / Vertex, CRISPR Therap - LARVOL DELTA

Early post-marketing safety signals of CRISPR-edited exagamglogene autotemcel (Casgevy) versus lentiviral betibeglogene autotemcel (Zynteglo): A faers disproportionality study, 2014–2025 (ASH 2025) - "This first FAERS-based safety analysis of CRISPR-edited therapy suggests Casgevy may be associated with early post-infusion gastrointestinal/mucosal and bleeding events, while Zynteglo shows a broader haematologic and vascular signal profile, with isolated liver and immune AEs. These disproportionate reporting signals, although preliminary, support enhanced clinical vigilance, especially for mucosal toxicity and bleeding. Limitations include small case counts, underreporting biases in FAERS, absent exposure denominators, and potential misclassification from manual PT grouping."

Clinical • P4 data • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Sickle Cell Disease

An automated platform for lentiviral transduction for HSC gene therapy promotes fitness of hematopoietic stem cells combined with higher transduction efficiency (ASH 2025) - "Although therapies for HSC gene therapy have been recently approved (Zynteglo™, Lyfgenia™ and Casgevy®), still certain challenges remain associated with high costs, scalability and safety related to leukemic events. Notably, low-density lipoprotein receptor (LDL-R), the cellular receptor that serves for the recognition by the VSV glycoprotein, was accordingly upregulated in cells processed on the CliniMACS Prodigy. These results suggest that the CliniMACS Prodigy promotes higher stemness or better fitness of HSCs while simultaneously allowing for higher transduction efficiencies due to downregulation of immune related pathways and upregulation of cholesterol and sterol binding."

Gene therapy • IO biomarker • Dyslipidemia • Gene Therapies • Immunology • Infectious Disease • CD34 • TLR8

Kilimanjaro challenge: The use of red blood cell functional assessment in a gene-edited sickle cell disease patient to predict response to extreme altitude conditions (ASH 2025) - "In a groundbreaking milestone, a 39-year-old male treated with exagamglogene autotemcel (Casgevy) in 2020 became the first SCD individual to summit Mount Kilimanjaro (19,341 ft) on September 16, 2024, at 7:30 a.m. The ascent, lasting 5.5 days, involved exposure to extreme hypoxic conditions (10.1% effective oxygen at the summit), temperatures ranging from -10 to -20 degrees Celsius... Hemoglobin profiles were stable pre- and post-summit: 45% HbS, 1% HbA₂, and 54% HbF. RBCs with detectable HbF were nearly 100% at both time points. DSA demonstrates the impact of induced hypoxia on sickling kinetics."

Clinical • Genetic Disorders • Hematological Disorders • Hepatology • Leukopenia • Sickle Cell Disease • HBB • VCAM1

Correction of ineffective erythropoiesis and durable clinical benefit with exagamglogene autotemcel for transfusion-dependent β-thalassemia (ASH 2025) - " CLIMB-111 is an ongoing 2-y, Phase 3 trial of exa-cel in TDT pts aged 12-35 y. The primaryendpoint is transfusion independence defined as proportion of pts maintaining a weighted averagehemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 consecutive months (m; TI12)...Consistent with that, there were 7 cases(7/56; 12.5%) of hepatic veno-occlusive disease; none resulted in end-organ dysfunction, all were relatedto busulfan and all resolved after defibrotide treatment... Exa-cel demonstrated durable clinical benefit for up to 6 y in adults and adolescents withTDT. After exa-cel, iron was successfully removed by IRT with no evidence of iron reaccumulation after IRTcessation. This suggests that in addition to durable TI in 98% of subjects, exa-cel potentially preventstissue iron deposition by restoring iron homeostasis via correction of underlying IE."

Clinical • Beta-Thalassemia • Genetic Disorders • Hepatology • ERFE

Non-genotoxic conditioning to increase donor chimerism levels in a mismatched murine transplant model for sickle cell disease (ASH 2025) - "The recently FDA-approved gene therapies Lyfgenia and Casgevy also employ MAC...We first investigated theefficiency of CD45- and CD117-sap as conditioning agents compared to classical total body irradiation(TBI) and busulfan. Our base conditioning regimen also included post-transplant cyclophosphamide (PT-Cy) and sirolimus...HPLC analysis at 20 weeks post-HCT showed that recipients conditioned with CD117-sapexhibited donor-derived Hb, while recipients conditioned with 200cGy TBI showed mixed donor/recipientHb. Furthermore, BM analysis at 24 weeks post-HCT also showed a significant increase in the frequenciesof donor-derived short- (52.50±5.67% vs 4.80±2.40%, p=0.0010) and long-term (43.28±5.79% vs0.79±0.79%, p=0.0016) hematopoietic stem cells in CD117-sap conditioned recipients, which furtherconfirms the successful long-term engraftment of CD117-sap conditioned recipients.In summary, CD117-sap, in combination with anti-thy1.2, PT-Cy, and sirolimus, is..."

Preclinical • Anemia • Gene Therapies • Genetic Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • KIT • PTPRC • THY1

Provider practices and preparedness for gene therapy in pediatric sickle cell disease: A national survey of pediatric hematologists (ASH 2025) - "In 2023, the FDA approvedtwo autologous gene therapies for patients ≥12 years old with recurrent vaso-occlusive crises (VOCs):lovotibeglogene autotemcel (Bluebird Bio) and exagamglogene autotemcel (Vertex/CRISPR Therapeutics).Despite their promise, integration into routine care remains challenging due to strict trial criteria andlimited implementation guidance. This national survey highlights substantial variability in gene therapy referral practices forpediatric sickle cell disease, particularly in cases involving neurologic complications and across differentprovider types. While hematologists with a SCD-focused practice reported greater comfort with GTcounseling, they were less likely to recommend GT in certain high-risk scenarios. These findingsemphasize the urgent need for standardized, evidence-based guidelines and targeted provider educationto ensure equitable access and appropriate integration of GT into pediatric SCD care."

Clinical • Gene therapy • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Pediatrics • Sickle Cell Disease

Evaluating the efficacy and safety of gene therapy in transfusion-dependent β-thalassemia: A focus on hemolysis improvement and clonal hematopoiesis monitoring (ASH 2025) - "The patient underwent autologousGT with CRISPR-Cas9–based gene editing (exagamglogene autotemcel, Vertex/CRISPR Therapeutics) onMarch 17, 2025, following a splenectomy to optimize engraftment. Conditioning with IV busulfan was welltolerated and no veno-occlusive disease observed...The risks observed in SCDare contrasted, and the importance of CH screening in optimizing patient selection is proposed. Long-term outcomes related to improvement of hemolysis and the potential for clonal expansion are alsohighlighted."

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Malignancies • Hepatology • Neutropenia • Sickle Cell Disease • CD34 • DNMT3A • HBB • HPX

Long-term follow-up demonstrates durable clinical benefits of exagamglogene autotemcel for sickle cell disease with recurrent vaso-occlusive crises: Final results of climb SCD-121 (ASH 2025) - "The completed CLIMB SCD-121 trial demonstrates elimination of VOCs after exa-cel in 91.1%of evaluable pts. 100% of pts achieved VOC free in CLIMB SCD-121 and CLIMB-131 combined, which wasmaintained long-term for up to 5.6 years. All pts had durable increases in Hb and HbF levels and stableallelic editing; clinically meaningful improvements were also seen in hemolysis markers and QOLmeasures."

Clinical • Bone Marrow Transplantation • Genetic Disorders • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Sickle Cell Disease • HP

Engineered extracellular vesicles for In Vivo gene therapy in sickle cell disease (ASH 2025) - "In2023, the FDA approved two gene therapies for SCD: Casgevy and Lyfgenia. Our innovative approach has the potential to serve as a foundationaltechnology for a safer, more accessible, and non-viral gene therapy applicable to a broad range ofgenetic disorders. The successful completion of this project will generate critical proof-of-concept dataand enable us to pursue further translational development for in vivo gene therapy for SCD."

Gene therapy • Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD63

Multiplex base editing enhances fetal hemoglobin production in sickle cell disease erythroid cells (ASH 2025) - "Notably, the triple-edited cells expressed significantly moreHbF (84.6% HbF of total hemoglobins) compared to unedited cells (7.9% HbF) as well as those editedusing a CBE at BCL11A (40.6% HbF) or HBG alone (59.5% HbF) and exceeded HbF levels seen in cellsedited with the FDA-approved CRISPR-based therapy Casgevy (34.5% HbF)...Importantly, RNA-seq analyses of edited cells revealed notranscriptomic signs of genotoxicity or off-target stress beyond the biological effects of each individualedit, supporting the safety and modularity of this strategy.Together, this work defines a new class of combinatorial genome editing strategies that pair disease-corrective and cell output-enhancing variants to improve therapeutic potency and broaden theapplicability of genome editing. Future applications may include incorporating immune evasion, epitopeshielding, or antigen deletion into a single multiplex editing payload to generate functionally enhanced,transplantation-ready cell therapies."

Genetic Disorders • Hematological Disorders • Immunology • Sickle Cell Disease

First results of exagamglogene autotemcel in pediatric patients aged 5-11 years with transfusion-dependent β-thalassemia or sickle cell disease with recurrent severe vaso-occlusive crises (ASH 2025) - "Efficacy and safety data for pts aged 5-11 y from CLIMB THAL-141 and CLIMB SCD-151 areconsistent with data from exa-cel trials in pts aged ≥12 y. Exa-cel demonstrated clinical benefit inpediatric pts, with a safety profile consistent with busulfan myeloablative conditioning and autologoustransplant. These data support exa-cel as a potential one-time functional cure for children aged 5-11 ywith TDT and SCD, with potential additional benefit of treating early, prior to development of chronicdisease complications."

Clinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Hepatology • Pediatrics • Sickle Cell Disease • CD34

CTx001 for Geographic Atrophy: A Gene Therapy Expressing Soluble, Truncated Complement Receptor 1 (Mini-CR1). (PubMed, Ophthalmol Sci) - "These findings support its further development as a 1-time gene therapy for addressing complement overactivation in GA. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article."

Journal • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Gene Therapies • Macular Degeneration • Ophthalmology • Retinal Disorders • CR1

Application of the Failure Mode and Effects Analysis (FMEA) to the pharmaceutical process of CASGEVY®, an ex vivo Gene Therapy Medicinal Product for beta-thalassemia (PubMed, Ann Pharm Fr) - "This study presents an original FMECA applied to a process designed ex nihilo. While the method has its limitations, particularly concerning the inherent subjectivity of the ratings, a retrospective analysis, conducted after testing the process under real conditions, will be crucial to refine corrective actions."

Journal • Preclinical • Beta-Thalassemia • Gene Therapies • Genetic Disorders

In children with SCD, 11 patients have been dosed with CASGEVY in the Phase 3 CLIMB-151 clinical study, and all (4/4) patients with sufficient follow-up achieved the primary endpoint of being free from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12) (Businesswire) - "No patient experienced a VOC following infusion with CASGEVY, with the longest duration of VOC-free of approximately two years (range 3.2–24.1 months)."

P3 data • Sickle Cell Disease

Sarah Cannon Research Institute to Present Research on Advances in…Blood Disorders at 2025 ASH Annual Meeting & Exposition (Sarah Cannon Research Institute (SCRI))

Clinical data • Beta-Thalassemia • Chronic Graft versus Host Disease • Sickle Cell Disease

CRISPR Technology: Transforming the Future of Medicine and Diagnostics. (PubMed, Biochemistry) - "We also briefly discuss the ethical implications of CRISPR technology. While some fundamental challenges persist, the future of CRISPR is undoubtedly bright."

Journal • Review • Gene Therapies • Infectious Disease • Oncology • MYC • TP53

ToolGen…announced that the United States Patent and Trademark Office has issued U.S. Patent No. 12,473,559 related to ToolGen's core foundational technology—direct intracellular delivery of the CRISPR-Cas9 ribonucleoprotein (RNP) complex. (PRNewswire) - "Concurrently with this U.S. patent registration, ToolGen filed a patent-infringement lawsuit in the United States concerning the production and sale of CASGEVY. ToolGen believes that CASGEVY, the world's first CRISPR-based genome-editing therapy, practices technology claimed in the newly issued patent."

Corporate lawsuit • Patent • Beta-Thalassemia • Sickle Cell Disease

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes (ASH 2023) - " We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion..."

Clinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Severe Sickle Cell Disease (ASH 2023) - "Adults infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family, and functional well-being, pain experience, and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with SCD."

Clinical • HEOR • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Transfusion-Dependent Beta-Thalassemia (ASH 2023) - "Adults and adolescents infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family and functional well-being and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with TDT."

Clinical • HEOR • Beta-Thalassemia • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Pediatrics • Transplantation

Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia (ASH 2023) - "The CLIMB THAL-111 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to transfusion independence in >90% of pts with TDT and improved QOL. Safety profile of exa‑cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel has the potential to deliver a one-time functional cure to pts with TDT."

Acute Respiratory Distress Syndrome • Beta-Thalassemia • Dental Disorders • Febrile Neutropenia • Genetic Disorders • Hematological Disorders • Hemophagocytic lymphohistiocytosis • Immunology • Infectious Disease • Neutropenia • Pneumonia • Pulmonary Disease • Rare Diseases • Respiratory Diseases • Stomatitis • Thrombocytopenia • CD34

Exagamglogene Autotemcel for Severe Sickle Cell Disease (ASH 2023) - "The CLIMB SCD-121 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to elimination of VOCs in 95% of pts, elimination of inpatient hospitalization for VOCs in 100% of pts and improved QOL. Safety profile of exa‑cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel has the potential to deliver a one-time functional cure to pts with severe SCD."

Dental Disorders • Febrile Neutropenia • Genetic Disorders • Hematological Disorders • Infectious Disease • Neutropenia • Novel Coronavirus Disease • Respiratory Diseases • Sickle Cell Disease • Stomatitis • BCL11A • CD34

Introducing CASGEVY (exagamglogene autotemcel) (ASH 2023) - "Sponsored by Vertex Pharmaceuticals Inc."

Gene Therapies for Hemoglobinopathies: Efficacy, Cell Collection & Transfusion Support. (PubMed, Transfus Med Rev) - "The U.S. Food and Drug Administration (FDA) has approved GTs for both SCD and TDT: lovotibeglogene autotemcel (Lyfgenia) and exagamglogene autotemcel (Casgevy) in 2023 for SCD and betibeglogene autotemcel (Zynteglo) in 2022 and exagamglogene autotemcel (Casgevy) in 2024 for TDT. This article appraises the studies the FDA approvals were based upon, with comments on transfusion and stem collection regimens. The latter aspects highlighting variability in practice and the need for additional studies to optimize pretransfusion regimens and the collection process for successful GT."

Journal • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Sickle Cell Disease • Transplantation

Transformative Therapies for Sickle Cell Disease: A Global Stakeholder Perception Study on Advanced Cell Therapies (ASH 2024) - "Exagamglogene autotemcel(EA) was the preferred gene therapy (20%), followed by lovotibeglogene autotemcel(L) (16.7%), 63.3%had no preference. It highlights fertility preservation, access to QTC, risk of secondary malignancy and cost barriers critical factors in patient selection. Future research should focus on expanding the donor pool for HSCT, gathering long-term data on GT's safety and efficacy, and developing strategies to alleviate the financial burden associated with these TT."

Clinical • Metastases • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Pediatrics • Sickle Cell Disease