| Contributors: |
Consiglieri, G.; Tucci, F.; De Pellegrin, M.; Guerrini, B.; Cattoni, A.; Risca, G.; Scarparo, S.; Sarzana, M.; Pontesilli, S.; Mellone, R.; Gasperini, S.; Galimberti, S.; Silvani, P.; Filisetti, C.; Darin, S.; Forni, G.; Miglietta, S.; Santi, L.; Facchini, M.; Corti, A.; Fumagalli, F.; Cicalese, M. P.; Calbi, V.; Migliavacca, M.; Barzaghi, F.; Ferrua, F.; Gallo, V.; Recupero, S.; Canarutto, D.; Doglio, M.; Tedesco, L.; Volpi, N.; Rovelli, A.; La Marca, G.; Valsecchi, M. G.; Zancan, S.; Ciceri, F.; Naldini, L.; Baldoli, C.; Parini, R.; Gentner, B.; Aiuti, A.; Bernardo, M. E. |
| Description: |
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. |