Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency
Issued Date
2024-01-01
Resource Type
ISSN
15250016
eISSN
15250024
Scopus ID
2-s2.0-85207363597
Pubmed ID
39169621
Journal Title
Molecular Therapy
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Therapy (2024)
Suggested Citation
Pham V., Tricoli L., Hong X., Wongkittichote P., Castruccio Castracani C., Guerra A., Schlotawa L., Adang L.A., Kuhs A., Cassidy M.M., Kane O., Tsai E., Presa M., Lutz C., Rivella S.B., Ahrens-Nicklas R.C. Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency. Molecular Therapy (2024). doi:10.1016/j.ymthe.2024.08.015 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/101873
Title
Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency
Author's Affiliation
The Children's Hospital of Philadelphia
Universitätsmedizin Göttingen
Faculty of Medicine Ramathibodi Hospital, Mahidol University
The Jackson Laboratory
University of Pennsylvania
University of Pennsylvania Perelman School of Medicine
Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)
Universitätsmedizin Göttingen
Faculty of Medicine Ramathibodi Hospital, Mahidol University
The Jackson Laboratory
University of Pennsylvania
University of Pennsylvania Perelman School of Medicine
Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)
Corresponding Author(s)
Other Contributor(s)
Abstract
Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplantation with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.
