Preclinical studies to support the intrathecal delivery of scAAV9/SUMF1 as a gene replacement therapy for multiple sulfatase deficiency

Bailey, Rachel M.; Presa, Maximiliano; Ray, Somdatta; Bailey, Lauren; Coombs, Harold; Walls, Randy; Lutz, Cathleen; Gray, Steven J.

doi:10.1016/j.ymgme.2020.12.020

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 CNS-directed adeno-associated virus (AAV)-mediated SUMF1 gene replacement is also in preclinical development for MSD. 53,54 While brain-directed AAV gene therapy has shown promise in several preclinical models of neuronopathic lysosomal storage disorders, it may not address many somatic manifestations of MSD, such as orthopedic complications. 12,14 Currentlyutilized AAV capsids have a limited ability to target bone and cartilage.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency

Pham,

Tricoli,

Hong

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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 transplant 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency

Pham,

Tricoli,

Hong

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…MSD is an ultra-rare fatal degenerative disorder with emerging therapeutic options. 5,26,27 Until now, clinically meaningfully biomarkers for MSD have been lacking. In MSD, the activity of individual sulfatases only partially correlates with clinical severity.…”

Section: Discussionmentioning

confidence: 99%

“…MSD is an ultra‐rare fatal degenerative disorder with emerging therapeutic options 5,26,27 . Until now, clinically meaningfully biomarkers for MSD have been lacking.…”

Section: Discussionmentioning

confidence: 99%

Biochemical signatures of disease severity in multiple sulfatase deficiency

Adang,

Mowafy,

Herbst

et al. 2023

J of Inher Metab Disea

View full text Add to dashboard Cite

Sulfatases catalyze essential cellular reactions, including degradation of glycosaminoglycans (GAGs). All sulfatases are post‐translationally activated by the formylglycine generating enzyme (FGE) which is deficient in Multiple Sulfatase Deficiency (MSD), a neurodegenerative lysosomal storage disease. Historically, patients were presumed to be deficient of all sulfatase activities; however, a more nuanced relationship is emerging. Each sulfatase may differ in their degree of post‐translational modification by FGE, which may influence the phenotypic spectrum of MSD.Here, we evaluate if residual sulfatase activity and accumulating GAG patterns distinguish cases from controls and stratify clinical severity groups in MSD. We quantify sulfatase activities and GAG accumulation using three complementary methods in MSD participants. Sulfatases differed greatly in their tolerance of reduction in FGE‐mediated activation. Enzymes that degrade heparan sulfate (HS) demonstrated lower residual activities than those that act on other GAGs. Similarly, HS‐derived urinary GAG subspecies preferentially accumulated, distinguished cases from controls, and correlated with disease severity.Accumulation patterns of specific sulfatase substrates in MSD provide fundamental insights into sulfatase regulation and will serve as much‐needed biomakers for upcoming clinical trials. This work highlights that biomarker investigation of an ultra‐rare disease can simultaneously inform our understanding of fundamental biology and advance clinical trial readiness efforts.This article is protected by copyright. All rights reserved.

show abstract

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency

Pham,

Tricoli,

Hong

et al. 2024

Molecular Therapy

View full text Add to dashboard Cite

Preclinical studies to support the intrathecal delivery of scAAV9/SUMF1 as a gene replacement therapy for multiple sulfatase deficiency

Cited by 3 publications

References 0 publications

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency

Biochemical signatures of disease severity in multiple sulfatase deficiency

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency

Contact Info

Product

Resources

About