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Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

La mucopolisaccaridosi di tipo I (MPS-I) è una malattia da accumulo lisosomiale, dovuta alla carenza dell'enzima alfa-L-iduronidasi, determinando il progressivo accumulo di glicosaminoglicani (GAGs) negli organi. Il trapianto di cellule staminali ematopoietiche (HSCT) e la terapia di sostituzione enzimatica (ERT) sono le terapie attualmente disponibili per i pazienti affetti da MPS-I. Nonostante la loro efficacia nel correggere la maggior parte delle manifestazioni cliniche, le alterazioni muscolo-scheletriche e i difetti neurocognitivi influenzano ancora la qualità della vita dei pazienti anche dopo la terapia. Oggigiorno è ampiamente riconosciuto che un intervento precoce è di cruciale importanza per ottenere un migliore outcome clinico. Sulla base di queste osservazioni abbiamo testato l'efficacia terapeutica di HSCT e ERT, da soli o in combinazione, somministrati alla nascita, in un modello murino di MPS-I. Abbiamo dimostrato che tutti e tre i trattamenti sono in grado migliorare i parametri biochimici, ripristinando l’attività enzimatica e riducendo l’accumulo dei GAGs negli organi e nel plasma; in particolare, la terapia combinata ha dimostrato una maggiore efficacia negli organi più difficili da correggere, come i reni e il cuore. Abbiamo osservato solamente una moderata riduzione dell’infiammazione, senza una evidente correzione metabolica nel cervello. Per quanto riguarda invece il fenotipo scheletrico abbiamo riscontrato un effetto differenziale nella riduzione della patologia ossea, con una migliore correzione nei topi trapiantati. I nostri risultati dimostrano che la maggior parte delle manifestazioni patologiche possono essere prevenute, agendo in epoca neonatale, con un trattamento basato sulla combinazione di HSCT e ERT, promuovendo l'idea di un intervento precoce supportato dallo sviluppo di programmi di screening neonatali., Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder due to deficiency in the alpha-L-iduronidase enzyme, resulting in the progressive accumulation of glycosaminoglycans (GAGs) in multiple organs and the consequent multiorgan dysfunction. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are the currently available therapies for MPS-I patients. Despite their effectiveness in correcting most clinical manifestations, muscoloskeletal abnormalities and neurocognitive defects still impact quality of life of treated patients. It is widely accepted that an early intervention may be crucial to obtain a better outcome. On the basis of these observations, we tested the therapeutic efficacy of HSCT and ERT, alone or in combination, administered at birth, in a MPS-I mouse model. We demonstrated that all three treatments were able to prevent biochemical and pathological manifestations of the disease in visceral organs, and, in particular, the combination therapy had a better outcome in difficult-to-treat organs, such as kidney and heart. Of note, transplant procedure can halt the production of antibodies specific for the recombinant enzyme that could reduce ERT efficacy. Regarding the severe skeletal disease, we observed a differential effect in reduction of bone disease, with a significant better correction in transplanted mice, in the presence of ERT or not. Otherwise in the brain, all the treatments provided a moderate decrease of inflammation without an evident metabolic correction. Our findings demonstrate that most manifestations of MPS-I can be prevented by a neonatal treatment based on a combination of HSCT and ERT, promoting the idea of an early intervention supported by the development of newborn screening programs.

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.