First-in-human phase I/II clinical trial of hematopoietic stem and progenitor cell gene therapy for Hurler syndrome: Favorable safety profile and extensive metabolic correction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) +/− pre−/peri-transplant enzyme replacement therapy is standard of care for Hurler syndrome (MPS-IH). However, cognitive and skeletal abnormalities progress over time after allo-HSCT, severely affecting patient's quality of life. We report the interim results of a first-in-human phase I/II trial (NCT03488394) of 8 MPS-IH patients treated with autologous hematopoietic stem and progenitor cells (HSPC) genetically modified to overexpress human IDUA and followed-up for a median of 2.1 years after gene therapy (GT). Patients (6 M, 2 F; median age at treatment 24 months) lacked a non-heterozygous-HLA-matched cord blood donor and displayed IQ/DQ > 70. Primary efficacy endpoint was blood IDUA activity up to supraphysiologic levels at 1y post-GT. Clearance of lysosomal storage material, skeletal and neurophysiological development were assessed as secondary and exploratory endpoints. Mean drug product CD34+ cell dose was 20.9 × 106/kg with a median vector copy number of 2.2 per genome. All patients had rapid hematologic recovery with median neutrophil engraftment on day +20 and short periods of thrombocytopenia. The 5 patients positive for anti-IDUA antibodies before GT cleared them within 3 months after GT. The procedure was generally well tolerated. All patients showed sustained engraftment of gene-corrected cells with blood IDUA activity reaching supraphysiologic levels after GT in all patients, maintained at last follow-up. Urinary glycosaminoglycan (GAG) excretion levels reduced to normal or near-normal values by 1-year post-GT. IDUA activity in cerebrospinal fluid (CSF) became detectable by month 3 post-GT in all subjects accompanied by progressive decrease in CSF GAG storage. With a median follow-up of 2.1 years, patients show stable cognitive and motor performance, reduced joint stiffness, improved or stable findings on brain and spine MRI and normal growth according to peers. HSPC-GT accomplishes extensive metabolic correction and initial clinical response with a favorable safety profile, highlighting its therapeutic potential for MPS IH treatment.