PS1220 EX‐VIVO HEMATOPOIETIC STEM CELL GENE THERAPY (GT) FOR MUCOPOLYSACCHARIDOSIS TYPE I HURLER (MPSIH): PRELIMINARY RESULTS FROM A PHASE I/II CLINICAL STUDY
Authors: Bernardo M.E. , Gentner B. , Tucci F. , Fumagalli F. , Silvani P. , Filisetti C. , Redaelli D. , Acquati S. , Zonari E. , Rovelli A. , Parini R. , La Marca G. , Naldini L. , Aiuti A. 
Published: June 2019

Background:MPSIH is a lysosomal storage disease caused by α‐L‐iduronidase (IDUA) deficiency that is associated with progressive multisystem morbidity including neurodevelopmental deterioration and severe orthopedic manifestations, leading to death in early childhood. Current therapeutic strategies include enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation (HSCT), which however show limitations in preventing neurodevelopmental and orthopedic complications. Transplantation of genetically‐engineered autologous hematopoietic stem and progenitor cells (HSPC) is an attractive treatment option for MPSIH thanks to the possibility to obtain supraphysiologic levels of the missing enzyme in the hematopoietic progeny, thus allowing for increased cross‐correction.Aims:We recently opened a phase I/II clinical trial (NCT03488394) in children affected by MPSIH aimed at evaluating safety, tolerability and efficacy of the transplantation of autologous, IDUA lentiviral (LV)‐transduced CD34+ cells in MPSIH patients undergoing myeloablative conditioning.Methods:The study foresees the enrollment of 6 patients who lack a non‐heterozygous HLA‐matched donor and display an IQ/DQ>70. Primary endpoints of safety include: overall survival, hematological engraftment and safety of drug product (DP) administration. Primary endpoint of efficacy is represented by IDUA activity in peripheral blood up to supraphysiologic levels at 1 year post‐gene therapy (GT). Treatment impact on nervous system, skeleton and other target organs is assessed by clinical and radiologic parameters, as well as by disease‐specific biomarkers.Results:By the submission deadline, two patients (24 and 14 months old) were treated and have a follow‐up of 7 and 1.5 months, respectively. Autologous HSPC were harvested after mobilization with G‐CSF and Plerixafor; the procedure was uneventful and resulted in cryopreserved DP of 24 and 14 million CD34+ cells/kg, respectively. Transduction efficiency in the drug products was above 80% using an optimized transduction protocol that preserved engraftment potential of ex vivo‐cultured HSPC in preclinical models. No adverse events related to DP infusion were recorded. Hematopoietic engraftment was fast in both patients; neutrophil engraftment occurred on day +17 and +22, respectively; platelet engraftment at day+15 with counts never falling below 30.000/ul in both patients. Importantly, both patients reached supraphysiologic levels of IDUA by day+14 that stabilized around 10 fold above the mean of the normal range, along with an in vivo vector copy number ranging from 2 to 4 in multiple hematopoietic lineages. At the 6 month follow‐up of patient 1, stable IDUA activity was detected in the cerebrospinal fluid, and urinary GAGs normalized. A third patient has been successfully mobilized resulting in a cryopreserved DP of 13 million CD34+ cells/kg and will be treated shortly. Other patients are currently under evaluation.Summary/Conclusion:Preliminary clinical results indicate that our optimized transduction protocol allows efficient HSPC transduction without compromising their engraftment potential. Treated patients showed rapid hematopoietic recovery, supraphysiologic IDUA levels in the peripheral blood and metabolic correction of the MPSI‐H enzyme defect in critical target tissues. Long term‐follow up and treatment of further patients are necessary to confirm that IDUA supraphysiologic levels result in improvement of neurological and orthopedic outcome as compared to allogeneic HSCT.