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

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

Background: Thalassemia represents the world’s most prevalent inherited hemoglobin disorder, affecting approximately 4.4 per 10,000 live births globally. Accurate genetic characterization is indispensable both for definitive diagnosis and for lifetime clinical monitoring. The past two decades have witnessed a paradigm shift from conventional protein-based assays toward comprehensive molecular techniques, including next-generation sequencing (NGS), third-generation (long-read) sequencing, and preimplantation genetic testing for monogenic disease (PGT-M). Objectives: (1) To systematically evaluate the molecular techniques available for confirming the diagnosis of alpha- and beta-thalassemia, including their diagnostic accuracy, indications, and limitations; (2) to examine how genotype–phenotype correlation and genetic modifier profiling inform clinical prognosis and therapeutic decision-making; and (3) to define evidence-based genetic monitoring parameters for longitudinal follow-up of patients receiving transfusions, iron chelation, and novel curative therapies including gene therapy. Methods: A comprehensive narrative review was conducted by systematically searching PubMed/MEDLINE for English-language peer-reviewed articles published between January 2000 and December 2024. Forty-three studies were ultimately included after applying predefined inclusion and exclusion criteria. Quality of included studies was assessed using SANRA (Scale for the Assessment of Narrative Review Articles). Results: HPLC and capillary electrophoresis remain first-line phenotyping tools; DNA-based confirmation is mandatory for complete genotyping. NGS-based targeted panels detect >95% of common mutations but require MLPA co-testing or long-read sequencing for structural variants. Genotype–phenotype prediction is substantially enhanced by profiling three major modifier loci: XmnI (Gγ), BCL11A, and HBS1L-MYB. PGT-M using NGS achieves near-complete genotyping accuracy (>99%) with live birth rates of 40–60% per frozen embryo transfer cycle. For patients receiving curative gene therapy (exagamglogene autotemcel / Casgevy), molecular follow-up protocols spanning 15 years are now recommended. Cardiac T2* MRI remains the most reliable non-invasive tool for iron overload follow-up, superior to serum ferritin alone. Conclusion: A tiered, genotype-informed approach—combining HPLC/CE phenotyping, targeted molecular diagnostics, genetic modifier profiling, and periodic re-evaluation—optimizes diagnostic precision and guides individualized management across the thalassemia spectrum. Integration of PGT-M and long-read sequencing into standard care pathways, alongside robust gene therapy follow-up protocols, will define the next era of thalassemia genetics.

Abstract licence: CC BY