Abstract: S102

Type: Presidential Symposium

Session title: Presidential Symposium

Background

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard of care for mucopolysaccharidosis type I Hurler (MPS-IH) patients showing high overall survival rates and high rate of full donor chimerism when patients are treated at young age and cord blood (CB) hematopoietic stem cells (HSC) are employed. In allo-HSCT, engrafted donor-derived cells constitute a stable endogenous source of the enzyme that can be distributed systemically. However, skeletal abnormalities persist and progress over time severely affecting patient’s quality of life together with progressive neurocognitive deterioration.

Aims

Here we report the results of a first-in-human phase I/II clinical trial (NCT03488394) of 8 MPSIH patients treated with autologous HSC genetically modified to overexpress human IDUA and followed-up for a maximum of 2 years (median 12 months).

Methods

Patients (6 M, 2 F; median age at treatment 24 months) lacked a non-heterozygous-HLA-matched CB donor and displayed an IQ/DQ>70. Seven out of 8 patients received enzyme replacement therapy before gene therapy (GT) and 5 of them had a positive anti-IDUA IgG titer at baseline. A high number of autologous HSCs was collected by leukapheresis following mobilization and were transduced with a clinical-grade lentiviral vector encoding human IDUA cDNA. Primary endpoint of efficacy was IDUA activity in dried blood spot up to supraphysiologic levels at 1y post-GT. Treatment impact on nervous system and bone was assessed by biochemical, clinical and radiologic parameters.

Results

Median cell dose was 20.7 CD34+/Kg with a median transduction efficiency above 80% and a median vector copy number (VCN) per cell of 2.2 in the drug products. All patients had rapid hematologic recovery, with median neutrophil engraftment on day +20.5 and short thrombocytopenia limited to grade 3 in most patients. The 5 patients that tested positive for IDUA antibodies before GT cleared them within 3 months after GT. Adverse events were generally mild and comparable to those seen with autologous-HSCT, with the exception of one patient who experienced an acute allergic reaction on day+12 which promptly resolved. Gene-marked cells appeared in the bone marrow and peripheral blood in all patients as early as day+30 after GT and were accompanied by achievement of   blood IDUA activity to supraphysiological levels in all patients, maintained at 12 months follow-up. All patients had a steep decline in urinary heparan sulfate (HS) and dermatan sulfate (DS) reaching normal or near-normal values by 1 year after treatment. Importantly, undetectable cerebrospinal fluid (CSF) IDUA activity at baseline became detectable by month 3 in all subjects and further increased by month 6 suggesting central enzyme expression, likely provided by local engraftment of microglia-like cells derived from transduced HSC. HS and DS levels in the CSF decreased post-GT suggesting central metabolic correction. With a median follow-up of 12 months, patients show stable cognitive and language performances, stable motor skills corresponding to continued motor development, improved joint stiffness and growth according to expected height percentiles of normal subjects. Brain and spine MRI showed improvements in some of the typical disease features at 1-year follow-up.

Conclusion

These results suggest that GT accomplishes extensive metabolic correction of peripheral and central compartments and promising preliminary clinical outcomes together with a favorable safety profile, highlighting the therapeutic potential of HSC-GT for the treatment of MPSIH.

Keyword(s): Gene therapy, Hematopoietic stem and progenitor cells, Lentivirus