Lentiviral gene therapy for Mucopolysaccharidosis II with tagged IDS prevents life threatening pathology in peripheral tissues but fails to correct cartilage.
Catalano F, Vlaar EC, Dammou Z, Katsavelis D, Huizer TF, Zundo G, Hoogeveen-Westerveld M, Oussoren E, van den Hout HJMP, Schaaf G, Pike-Overzet K, Staal F, Van Der Ploeg A, Pijnappel WWMP
Human gene therapy, 2023 Dec 12
Abstract
Deficiency of Iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II, a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with IGF2 or ApoE2, but not RAP12x2, efficiently prevented brain pathology in a murine model of MPS II. Here we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete (IDS.ApoE2co) or no (IDSco and IDS.RAP12x2co) correction. In contrast, tracheal, epiphyseal and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.