Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage

Fabio Catalano, Eva C. Vlaar, Zina Dammou, Drosos Katsavelis, Tessa F. Huizer, Giacomo Zundo, Marianne Hoogeveen-Westerveld, Esmeralda Oussoren, Hannerieke J. M. P. van den Hout, Gerben Schaaf, Karin Pike-Overzet, Frank J. T. Staal, Ans T. van der Ploeg, W. W. M. Pim Pijnappel

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Abstract

Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS 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 insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, 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.
Original languageEnglish
Pages (from-to)256-268
Number of pages13
JournalHuman Gene Therapy
Volume35
Issue number7-8
Early online date2 Feb 2024
DOIs
Publication statusPublished - 1 Apr 2024

Bibliographical note

Publisher Copyright:
© Fabio Catalano et al. 2024; Published by Mary Ann Liebert, Inc.

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