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Abstract 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.

Umbilical Cord blood is an intuitively attractive stem cell source, but its use has declined since it is associated with an increased procedure-related morbidity and transplant related mortality. Some of this reflects that cord blood transplants are more often HLA-mismatched compared to other unrelated donor transplants. The ability to transplant in such a setting, indeed without high rates of chronic Graft versus Host Disease (GVHD), constitutes an advantage compared to other unrelated donor cell sources and there are other advantages specifically associated with cord blood as a donor cell source. These advantages must be weighed against its disadvantage, and we have utilised cord blood preferentially as a donor cell source in certain clinical situations in paediatric medicine. In non-malignant diseases, outcomes in metabolic disease are critically dependent on age at transplant and the enzyme delivered by that transplant, and in cord blood transplantation then the time to transplant can be minimised and the engrafted recipients have higher chimerism that delivers higher enzyme levels. In malignant diseases, studies have described reduced relapse rate and better GVHD-free survival, and so we have prioritised cord as a donor cell source where the risk of relapse is highest, and the effects of higher transplant related mortality is most clearly offset by the reduced relapse rates.

Hematopoietic stem cell gene therapy is a promising therapeutic strategy for the treatment of neurological disorders, since transplanted gene-corrected cells can traffic to the brain, bypassing the blood-brain barrier, to deliver therapeutic protein to the CNS. We have developed this approach for the treatment of Mucopolysaccharidosis type IIIA (MPSIIIA), a devastating lysosomal storage disease that causes progressive cognitive decline, leading to death in early adulthood. In a previous pre-clinical proof-of-concept study, we demonstrated neurological correction of MPSIIIA utilizing hematopoietic stem cell gene therapy via a lentiviral vector encoding the SGSH gene. Prior to moving to clinical trial, we have undertaken further studies to evaluate the efficiency of gene transfer into human cells and also safety studies of biodistribution and genotoxicity. Here, we have optimized hCD34+ cell transduction with clinical grade SGSH vector to provide improved pharmacodynamics and cell viability and validated effective scale-up and cryopreservation to generate an investigational medicinal product. Utilizing a humanized NSG mouse model, we demonstrate effective engraftment and biodistribution, with no vector shedding or transmission to germline cells. SGSH vector genotoxicity assessment demonstrated low transformation potential, comparable to other lentiviral vectors in the clinic. This data establishes pre-clinical safety and efficacy of HSCGT for MPSIIIA.