Exagamglogene autotemcel 4million-13million cells/ml dispersion for infusion vials

Abstract Objective To understand the benefit-risk profile for historical and current treatments for MLD. Methods A systematic review was conducted on the effectiveness, safety, and costs of MLD treatments: allogeneic haematopoietic stem cell transplantation (HSCT) and atidarsagene autotemcel (arsa-cel) according to best practice. Results A total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients.LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients. Conclusions Overall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies.

Abstract licence: CC BY 4.0

Background: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) remain major global health burdens. Ex vivo gene-editing therapies aim to achieve durable fetal hemoglobin (HbF) induction or direct mutation correction. Methods: We systematically reviewed clinical studies of CRISPR-Cas9 or base-editing therapies for SCD and TDT (MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, conference proceedings; 2010–03 December 2025). Eleven studies (>170 treated patients) reporting post-infusion outcomes were included. Results: All therapies produced robust, pancellular HbF (30–65%) and total hemoglobin in/near the normal range. In TDT (n > 100 evaluable), transfusion independence (≥12 months, Hb ≥9 g/dL) was achieved in 89–100% across platforms, sustained up to >4 years. In SCD (n > 60 evaluable), adjudicated vaso-occlusive crises were eliminated for ≥12 months in ≥97% of patients treated with exagamglogene autotemcel and 100% in smaller cohorts (EDIT-301, BEAM-101). No graft failures occurred. Serious adverse events and one death were attributable to busulfan conditioning, not editing. No therapy-related malignancies or confirmed harmful off-target edits have been reported, although follow-up remains limited (median ~18 months, longest >4 years). Conclusion: Current evidence from phase 1–3 trials demonstrates that ex vivo gene editing can achieve functional cure for many patients with TDT and severe SCD. Conditioning-related toxicity, limited long-term safety data, and delivery complexity remain critical barriers to broader implementation.

Abstract licence: CC BY

ABSTRACT Introduction Sickle cell disease is the most common hereditary hemoglobinopathy followed by beta-thalassemia. Until recently, allogeneic stem cell transplantation was the only curative approach. Based on the Crispr-Cas9-technology enabling targeting specific genes of interest, fetal hemoglobin which is normally shut-off after birth can be switched on and sufficient levels can alleviate symptoms in sickle cell disease and avoid transfusions in beta-thalassemia. Two first-in-human clinical studies in sickle cell disease and beta-thalassemia aiming to increase the level of fetal hemoglobin by using Crispr-Cas9 to modify autologous hematopoietic stem cells in patients aged 12–35 years have proved safety and efficacy and have shown promising clinical outcomes. Areas covered The paper summarizes the outcome of the results of the two recently published clinical studies and compares them with the other available curative approaches. Expert opinion Based on the currently available safety and efficacy data of the two published clinical results on gene therapy with Crispr-Cas9 modified autologous stem cells (exagamglogene autotemcel), it can be anticipated that this approach will add significantly to the therapeutic options for patients with sickle cell disease and beta-thalassemia and can be considered for all patients above 12 years of age independent of a suitable allogeneic stem cell donor.

Abstract licence: CC BY-NC-ND 4.0

In the last few years, gene therapy, holding the promise for long-term disease correction through a one-time treatment, has transitioned from experimental research to approved medicine. Several gene therapies are now available for congenital blood disorders, notably for hemophilia and hemoglobinopathies. In this review, we discuss each of the six therapies that now have regulatory approval for treatment in the United States: Roctavian (valoctocogene roxaparvovec) for hemophilia A, Beqvez (fidanacogene elaparvovec) and Hemgenix (etranacogene dezaparvovec) for hemophilia B, Lyfgenia (lovotibeglogene autotemcel) for sickle cell disease, Zynteglo (betibeglogene autotemcel) for β-thalassemia, and Casgevy (exagamglogene autotemcel) for either sickle cell disease or β-thalassemia. The underlying principles for these treatments vary and include both in vivo and ex vivo methods, lentiviral and adeno-associated viral (AAV) vectors, and gene silencing by the CRISPR-Cas9 gene editing system. Consequently, they pose correspondingly disparate risks and benefits when compared to other treatment modalities and to each other. Although long-term effects are not yet entirely understood, given the novelty of these therapies, knowledge on patient outcomes is continuously increasing. Overall, results are very encouraging, often freeing patients from the need for coagulation factor or red blood cell (RBC) infusions, albeit that for some of these diseases there is room for further improvement in terms of safety and therapeutic durability, which may be achieved with next-generation gene therapy products. However, improvements are needed to address issues with durability of results, side effects, and accessibility of these therapies.

Abstract licence: CC BY-NC

Allogeneic hematopoietic cell transplantation (HCT) has been used for decades to treat certain malignant and non-malignant hematological conditions, but challenges remain. Increased understanding of disease mechanisms and recent developments in genome editing have enabled alternative strategies utilizing gene-edited autologous HCT and many of these have progressed to the clinic. We present here a comprehensive review of clinical trials of gene-edited autologous hematopoietic stem cells for the treatment of hemoglobinopathies and immunodeficiencies. Searches of major international clinical trial registries were carried out using specific key words. In total, 44 interventional clinical trials investigating gene-edited autologous stem cell therapies were identified, with CASGEVY (exagamglogene autotemcel) being the only product approved to date. Hemoglobinopathies were the most common indication (n = 37) followed by immunodeficiencies (n = 4), with single trials in HIV-1 infection, pyruvate kinase deficiency and limb-girdle muscular dystrophy. Gene-editing strategies fall into three categories: disruption of the BCL11A erythroid enhancer, editing of the γ-globin promoter and direct correction or disruption of disease-relevant genes. CD34+ hematopoietic stem and progenitor cells are the most common cell types edited, and CRISPR-Cas9 is the most widely used gene-editing modality. While results are encouraging, efficient intracellular delivery of gene-editing tools, editing efficiencies and off-target editing remain challenges for the field.

Abstract licence: CC BY