Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome

• DOI: 10.1126/scitranslmed.adi8214
• Publication Date: 2024-05-01T17:59:05Z
• Authors: Giulia Consiglieri; Francesca Tucci; Maurizio De Pelle...; Barbara Guerrini; Alessandro Cattoni; Giulia Risca; Stefano Scarparo; Marina Sarzana; Silvia Pontesilli; Renata Mellone; Serena Gasperini; Stefania Galimberti; Paolo Silvani; Chiara Filisetti; Silvia Darin; Giulia Forni; Simona Miglietta; Ludovica Santi; Marcella Facchini; Ambra Corti; Francesca Fumagalli; Maria Pia Cicalese; Valeria Calbi; Maddalena Migliav...; Federica Barzaghi; Francesca Ferrua; Vera Gallo; Salvatore Recupero; Daniele Canarutto; Matteo Doglio; Lucia Tedesco; Nicola Volpi; Attilio Rovelli; Giancarlo la Marca; Maria Grazia Vals...; Stefano Zancan; Fabio Ciceri; Luigi Naldini; Cristina Baldoli; Rossella Parini; Bernhard Gentner; Alessandro Aiuti; Maria Ester Bernardo
• Keywords: Male; Mucopolysaccharidosis I; Hematopoietic Stem Cell Transplantation; Infant; Genetic Therapy; Hematopoietic Stem Cells; Magnetic Resonance Imaging; Bone and Bones; Mucopolysaccharidosis, Hurler syndrome, growth, bone; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Child, Preschool; Humans; Female; Hurler syndrome; MPSI; lysosomal storage diseases; Child

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.