학술논문
Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome
Document Type
Article
Author
Consiglieri, Giulia; Tucci, Francesca; De Pellegrin, Maurizio; Guerrini, Barbara; Cattoni, Alessandro; Risca, Giulia; Scarparo, Stefano; Sarzana, Marina; Pontesilli, Silvia; Mellone, Renata; Gasperini, Serena; Galimberti, Stefania; Silvani, Paolo; Filisetti, Chiara; Darin, Silvia; Forni, Giulia; Miglietta, Simona; Santi, Ludovica; Facchini, Marcella; Corti, Ambra; Fumagalli, Francesca; Cicalese, Maria Pia; Calbi, Valeria; Migliavacca, Maddalena; Barzaghi, Federica; Ferrua, Francesca; Gallo, Vera; Recupero, Salvatore; Canarutto, Daniele; Doglio, Matteo; Tedesco, Lucia; Volpi, Nicola; Rovelli, Attilio; la Marca, Giancarlo; Valsecchi, Maria Grazia; Zancan, Stefano; Ciceri, Fabio; Naldini, Luigi; Baldoli, Cristina; Parini, Rossella; Gentner, Bernhard; Aiuti, Alessandro; Bernardo, Maria Ester
Source
Science Translational Medicine; May 2024, Vol. 16 Issue: 745
Subject
Language
ISSN
19466234; 19466242
Abstract
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.