Cell and gene therapy poses evolving challenges. The current article summarizes the discussions held by European Regional Committee of the International Society for Cell & Gene Therapy and the European Society for Blood and Marrow Transplantation (EBMT) on the current challenges in this field, focusing on the European setting. This article emphasizes the imperative assessment of real-world cell and gene therapy activity, advocating for expanded registries beyond hematopoietic transplantation and chimeric antigen receptor-T-cell therapy. Accreditation's role in ensuring standardized procedures, as exemplified by JACIE (The Joint Accreditation Committee of ISCT-Europe and EBMT), is crucial for safety. Access to commercial products and reimbursement variations among countries underscore the need for uniform access to advanced therapy medical products (ATMPs). Academic product development and point-of-care manufacturing face barriers to patient access. Hospital Exemption's potential, demonstrated by some initial experiences, may increase patient accessibility in individual situations. Regulatory challenges, including the ongoing European ATMPs legislation review, necessitate standardized criteria for Hospital Exemption and mandatory reporting within registries. Efforts to combat unproven therapies and fraud involve collaboration between scientific societies, regulatory bodies and patient groups. Finally, is important to highlight the vital role of education and workforce development in meeting the escalating demand for specialized professionals in the ATMP field. Collaboration among scientific societies, academic institutions, industry, regulatory bodies and patient groups is crucial for overcoming all these challenges to increase gene and cell therapy activity in Europe.

Metachromatic leukodystrophy (MLD) results from ARSA gene mutations. Affected individuals meet early milestones before neurological deterioration and early death. Atidarsagene autotemcel (arsa‐cel), an autologous haematopoietic stem cell gene therapy (HSC‐GT) product, has demonstrated sustained clinical benefits in MLD. Arsa‐cel was approved for NHS treatment in February 2022 for asymptomatic late infantile or early juvenile disease, or early symptomatic early juvenile MLD. We evaluate the impact of this approval in the largest real‐world dataset of MLD HSC‐GT. Hospital records were reviewed for all patients referred for NHS treatment following arsa‐cel approval. Information was gathered about disease phenotype, presentation, eligibility, and affected siblings. In the year following NHS approval, 17 UK MLD patients were referred for treatment. Four patients met eligibility criteria and have been treated, including 1 infant who weighed 5 kg at leukapheresis. Eleven patients failed screening: 10 symptomatic patients with late infantile disease and 1 with early juvenile disease and cognitive decline. Two further patients with later onset subtypes did not meet the approval criteria. Three out of four treated patients were diagnosed by screening after MLD was diagnosed in a symptomatic older sibling. The success of HSC‐GT for MLD has heralded a new era of hope for families affected by this devastating disease, yet currently, most patients are ineligible for treatment at diagnosis. The feasibility of apheresis in infants and the availability of a licenced, effective HSC‐GT product highlights the urgent need for newborn screening to ensure that patients can be diagnosed and treated before symptom onset.

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare, x-linked recessive, progressive, multi-system, lysosomal storage disease caused by the deficiency of iduronate-2-sulfatase (IDS), which leads to the pathological storage of glycosaminoglycans in nearly all cell types, tissues and organs. The condition is clinically heterogeneous, and most patients present with a progressive, multi-system disease in their early years. This article outlines the pathology of the disorder and current treatment strategies, including a detailed review of haematopoietic stem cell transplant outcomes for MPSII. We then discuss haematopoietic stem cell gene therapy and how this can be employed for treatment of the disorder. We consider how preclinical innovations, including novel brain-targeted techniques, can be incorporated into stem cell gene therapy approaches to mitigate the neuropathological consequences of the condition.

Lysosomal storage disorders are a group of multisystem monogenic conditions caused mostly by enzyme deficiencies which disrupt lysosomal functioning. Those which result in neuronal dysfunction are considered 'neuronopathic'. These neurodegenerative conditions, while individually rare, are collectively not uncommon, and are attractive targets for gene and cell-based therapies. In this review we describe the current landscape of such therapies in this group of disorders, where the more severe phenotypes manifest in children. We describe the conditions, the principles of cell therapy and gene therapy, and compare AAV and lentiviral approaches. This is a rapidly evolving area of medicine, and we highlight progress made, and the challenges that are ahead in bringing these therapies to all patients. Throughout, we offer real-world insight into delivering these therapies and suggest a way forward for the future; utilising combined therapies to bridge the obligate delays and increasing collaborative working practices in therapeutic development between clinicians, academics and industry.

Myeloid chimerism better reflects donor stem cell engraftment than whole-blood chimerism in assessing graft function following allogeneic hematopoietic stem cell transplant (HCT). We describe our experience with 130 patients aged younger than 18 years, treated with allogeneic HCT using bone marrow or PBSC from HLA-matched donors for non-malignant diseases, whose pre-transplant conditioning therapy included alemtuzumab and who were monitored with lineage-specific chimerism after transplant. At 6 years post-transplant, overall survival (OS) was 91.1% and event-free survival (EFS) was 81.5%, with no grade III-IV acute GvHD or chronic GVHD observed. Recipient T-cells did not contribute to graft loss. Mixed T-cell chimerism (MC) did not affect EFS, and there was no connection between T-cell chimerism and myeloid chimerism in patients with MC or graft loss. MC significantly correlated with virus infection; more children with MC were CMV seropositive than those with complete chimerism (CC). Additionally, MC was more common in patients with CMV viramia post-transplant. CD8 T-cell reconstitution was affected by viral reactivation, including CMV, with CD8 T-cell counts higher in the MC group than in the CC group. Mixed T-cell chimerism is due to autologous, virus-specific, predominantly CD8, T-cell expansion, and is protective and not deleterious to the recipient.

Recently Zhang et al. ( 2024) published their study entitled “Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.” The authors present three metachromatic leukodystrophy (MLD) patients treated with gene therapy and claim stabilization or even improvement, despite advanced symptomatic disease stage. The metachromatic leukodystrophy initiative (MLDi) ( Schoenmakers et al., 2022), an international collaborative network and registry for MLD, urges caution in interpreting these results, as the evidence raises several critical concerns. These claims risk fostering false hope among MLD patients and their families, particularly given the significant gaps in the data provided ( Fig. 1).