Gene and cell therapy advances

Prof. Claire Booth (University College London, UK) discussed recent advances in gene therapy for inborn errors of immunity, including regulatory innovation for rare diseases [1]. She noted that this field remains one of the foundational test beds for the broader gene therapy landscape.

Inborn errors of immunity encompass more than 500 rare disorders that affect the development and function of the immune system. Many are treatable with allogeneic haematopoietic stem cell transplantation (HSCT), while some can be amenable to gene therapy, Prof. Booth explained. Some advantages of gene therapy include avoiding graft-versus-host disease, reducing conditioning requirements compared with HSCT, and avoiding long-term immunosuppression. Over the past 5 years, clinical outcomes have improved due to several process innovations, including the use of mobilised peripheral blood stem cells collected by apheresis, lentiviral (LV) transduction enhancers, and cryopreservation.

Prof. Booth presented recent clinical data demonstrating the durable efficacy and safety of LV-based gene therapy. One example is a cross-border trial (NCT03538899), in which low-exposure busulfan conditioning followed by infusion of lentiviral gene-corrected autologous CD34+ cells resulted in the generation of genetically corrected, functional T- and B-cells in infants with newly diagnosed Artemis-deficient severe combined immunodeficiency (ART-SCID) [2].

In certain primary immunodeficiencies, the T-cell compartment is predominantly affected, with clinical manifestations driven by T-cell dysfunction. In these cases, autologous gene-modified T-cell approaches may provide clinical benefit, explained Prof. Booth. Proof of concept has now been demonstrated for T-cell gene therapy in several conditions, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), CD40 ligand deficiency, Munc13-4 deficiency (familial haemophagocytic lymphohistiocytosis type 3; FHL3), perforin deficiency (FHL2), and X-linked lymphoproliferative disease (XLP). “Advantages of this approach include ease of cell collection, high transduction or editing efficiency, less intensive conditioning, and a potentially lower genotoxic risk compared with stem cell-based approaches,” noted Prof. Booth.

The first trial for IPEX syndrome is underway: a phase 1 study (NCT05241444) evaluating autologous reengineered CD4^LVFOXP3 regulatory T-cell (Treg-like) therapy. In patients with XLP-01, autologous T-cell gene therapy has been shown to correct SAP-dependent immune defects [3], including improvements in germinal centre formation, T-cell–dependent antibody responses, T follicular helper (TFH) cell function, in vitro cytotoxicity, and in vivo tumour clearance. These findings have paved the way for the upcoming XLP T01 clinical trial.

Prof. Booth concluded that while the benefit/risk profile is well established, challenges remain in health technology assessments to determine pricing and reimbursement at the country level, as well as in regulation through hospital exemption policies for gene and cell therapies [4]. Regulatory innovation for rare diseases is ongoing. The U.S. Food and Drug Administration (FDA) recently introduced the Rare Disease Evidence Principles (RDEP) to support accelerated evaluation of therapies for rare genetic diseases. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) has committed to major reforms in the regulation of advanced therapies [5], with a new framework for rare disease treatments expected in 2026.

Booth C. Gene therapy for inborn errors of immunity. P02-5, EBMT congress 2026, 22–25 March, Madrid, Spain.
Cowan MJ, et al. N Engl J Med. 2022;387(25):2344-2355.
Panchal N, et al. J Allergy Clin Immunol. 2018;142(1):235–245.E6.
https://op.europa.eu/o/opportal-service/PDF.
www.gov.uk/government/publications/rare-therapies-and-uk-regulatory-considerations/rare-therapies-and-uk-regulatory-considerations. Accessed 21 April 2026

Exagamglogene autotemcel (exa-cel) demonstrated durable clinical benefits with >6 years of follow-up in patients with transfusion-dependent β-thalassemia (TDT) or sickle cell disease (SCD). The safety profile was consistent with myeloablative busulfan conditioning and autologous transplantation, with no malignancies reported [1]. These data suggest that exa-cel has the potential to provide a one-time functional cure for TDT and SCD.

Exa-cel is a one-time, ex vivo CRISPR/Cas9 gene-edited autologous cell therapy approved for patients aged ≥12 years with TDT or SCD who have recurrent vaso-occlusive crises (VOCs). Prof. Franco Locatelli (University of Pavia, Italy) reported long-term efficacy and safety results from 3 phase 3 trials: CLIMB THAL-111 (NCT03655678), CLIMB-121 (NCT03745287), and the extension study CLIMB-131 (NCT04208529). Participants were aged between 12 and 35 years, with a mean age of approximately 21 years.

In CLIMB THAL-111, 56 participants with TDT received exa-cel. TDT was defined as a history of ≥100 mL/kg/year or ≥10 units/year of red blood cell (RBC) transfusions in the previous 2 years. The primary endpoint is transfusion independence (TI12), defined as maintaining a weighted average haemoglobin ≥9 g/dL without RBC transfusion for ≥12 consecutive months. In the combined CLIMB THAL-111 and CLIMB-131 analysis, 55 of 56 patients (98.2%) achieved TI12 after a median follow-up of 49.6 months. Transfusion independence was sustained for a median of 3.9 years. All participants achieved neutrophil and platelet engraftment.

In CLIMB-121, 46 participants with severe SCD and a history of ≥2 severe VOCs per year in the previous 2 years received exa-cel. The primary endpoint was the proportion of participants free of severe VOCs for ≥12 consecutive months (VF12). After a median follow-up of 44.7 months, all 46 evaluable participants achieved VF12 in CLIMB-121 and CLIMB-131 analysis. All participants also achieved neutrophil and platelet engraftment.

The safety of exa-cel was consistent with that expected for myeloablative busulfan conditioning and autologous transplantation in both TDT and SCD. In CLIMB THAL-111, 16 patients (28.6%) experienced adverse events (AEs) related to exa-cel, and 55 (98.2%) experienced AEs related to busulfan. In CLIMB-121, 13 patients (28.3%) and 46 patients (100%) experienced AEs related to exa-cel and busulfan, respectively. No malignancies were reported during follow-up in CLIMB-131.

“Long-term follow-up continues to demonstrate that exa-cel has the potential to provide a one-time, durable treatment benefit for patients with SCD and TDT,” concluded Prof. Locatelli.

Locatelli F, et al. Durable clinical benefits with exagamglogene autotemcel for greater than 6 years of follow-up in transfusion-dependent thalassemia and sickle cell disease with recurrent vaso-occlusive crises. GS2-5, EBMT congress 2026, 22–25 March, Madrid, Spain.

Recent advances in gene therapy for inborn errors of immunity

Gene-edited autologous cell therapy in patients with TDT or SCD