Ex vivo hematopoietic stem cell gene therapy for mucopolysaccharidosis type I (Hurler syndrome)

Transplantation of genetically-corrected autologous hematopoietic stem and progenitor cells (HSPC) represents a promising treatment approach for patients with lysosomal storage disorders. We conducted a phase I/II gene therapy (GT) study in children affected by Hurler syndrome. Eight patients were infused with autologous HSPC transduced with an alpha-L-iduronidase (IDUA)- encoding lentiviral vector following conditioning with busulfan and fludarabine. Seven of 8 patients had previous enzyme replacement therapy (ERT), which was discontinued several weeks before GT. Median transduction efficiency of the products was above 80%, with a median of 2.2 vector copies (VCN) per cell. All patients had rapid hematologic recovery, with median neutrophil engraftment on day +20, rapid resolution of neutropenic fever (median: 1.5 days) and short thrombocytopenia limited to grade 3 in most patients. GT did not induce IgG immune responses to IDUA, and the 5 patients that tested positive for antibodies while on ERT before GT, cleared them within 3 months. With a median follow up of 17 months (range: 9–26) as of October 2020, all patients are alive and well and show evidence for stable, polyclonal gene marking (median VCN in granulocytes: 1.4). Notably, patients show extensive enzymatic reconstitution, with supraphysiologic median blood IDUA activity of 111 micromol/L/h (normal range: 3.8–35) accompanied by normalization of urinary glycosaminoglycan (GAG) levels. Importantly, IDUA activity was detectable in the cerebrospinal fluid (CSF) suggesting central enzyme expression, likely provided by local engraftment of microglia-like cells derived from transduced HSPC. Heparan sulfate levels in the CSF decreased up to 20-fold post-GT suggesting central metabolic correction. Patients with the longest follow-up demonstrated a stable cognitive score, improved findings on brain and spine MRI, resumed growth velocity and an amelioration of their skeletal phenotype. Our preliminary results show encouraging safety and efficacy data, highlighting the potential of genetic engineering of HSPC for the treatment of MPSI.