Non-neurological, non skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy -OTL-203- for Hurler syndrome.

Patients with Mucopolysaccharidosis type I Hurler (MPSIH) experience multisystem clinical manifestations which are only partially addressed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study evaluated outcomes from a lentiviral vector (LV)-mediated hematopoietic stem and progenitor cell gene therapy (HSPC-GT) trial (NCT03488394) in 8 MPSIH patients followed up to 4 years post-treatment. Key findings included corneal clouding, hearing loss (HL), carpal tunnel syndrome (CTS) and cardiac evaluations. A retrospective comparison with an external cohort of 9 MPSIH patients undergoing allo-HSCT was performed. All patients are alive at last follow-up, show stable engraftment without graft failure, insertional oncogenesis, or immune responses to the transgene. Notably, at last follow-up 3/8 HSPC-GT patients experienced corneal clouding resolution, while all allo-HSCT patients maintained moderate corneal clouding. 4/8 HSPC-GT patients showed normal hearing function at last follow-up due to improvement (n=3) or stabilization (n=1); 7/9 allo-HSCT patients had mild or moderate HL at baseline, while 2/9 showed moderate HL at last follow-up. No HSPC-GT patients required surgery for CTS developed after HSPC-GT, while 7/9 patients needed such surgery after allo-HSCT. No HSPC-GT patients developed severe cardiomyopathy or valvular disease, while in the HSCT cohort 4/9 patients experienced progression of valvular insufficiency although not requiring valve replacement. Our results indicate a favorable effect of HSPC-GT on MPSIH multisystemic manifestations up to 4-year after treatment; long-term, prospective comparative studies are warranted for definitive conclusions.