Endogenous, non-reducing end glycosaminoglycan biomarkers are superior to internal disaccharide glycosaminoglycan biomarkers for newborn screening of mucopolysaccharidoses and GM1 gangliosidosis

Herbst, Zackary M.; Hong, Xinying; Urdaneta, Leslie; Klein, Terri; Waggoner, Christine; Liao, Hsuan-Chieh; Kubaski, Francyne; Giugliani, Roberto; Fuller, Maria; Gelb, Michael H.

doi:10.1016/j.ymgme.2023.107632

Cited by 7 publications

(9 citation statements)

References 27 publications

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“…A hallmark feature of MSD and related single-sulfatase disorders is the accumulation of GAGs in patient cells and tissues due to the inability of sulfatases to break them down. 36 We detected six different GAG subspecies in MSD cells that all showed significant accumulation compared to WT cells by mass spectrometry using the endogenous, non-reducing end (NRE) biomarker method ( Figures 2A-D ). 36,37 These GAG subspecies are associated with MPS I/II, IIIA, IIID, and VI, single-sulfatase disorders closely related to MSD.…”

Section: Resultsmentioning

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

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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.

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Section: Resultsmentioning

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

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“…Neurons derived from iPSCs by overexpressing NGN2 have been extensively used to investigate the processes of neuronal differentiation and to create models of neurological disorders [29]. We produced MSD and isogenic control NGN2-iNs by differentiating iPSCs using established protocols [26,27]. NGN2-iNs were collected for analyses at Days 3 (D3 NGN2-iN) and 11 (D11 NGN2-iN) of differentiation in order to compare phenotypes during neuronal development.…”

Section: Resultsmentioning

confidence: 99%

“…Functional deficiencies in FGE and downstream sulfatases lead to the accumulation of GAGs in MSD patient cells and animal models. To investigate whether GAGs accumulate in our MSD iPSC, NPC, and NGN-iN cell models, we quantified GAG subspecies by mass spectrometry using the endogenous, non-reducing end (NRE) biomarker method [26,27]. (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…GAG fragments (i.e., sulfated oligosaccharides) in cells were measured using a modified protocol as described [26,27]. Chondroitin disaccharide di-4S (dUA-GalNAc-4S, Biosynth) was used as the internal standard (IS).…”

Section: Methodsmentioning

confidence: 99%

“…The UPLC-MS/MS analysis was carried out on a Waters TQ-S tripe quadrupole mass spectrometry coupled to an ACUIQTY Classic UPLC system. Three previously reported markers, HexN-UA-1S (MPS-IIIA), GlcNAc-6S (MPS-IIID), and GalNAc-4S (MPS-VI), were analyzed [26,27]. Two novel markers, UA-HexN-UA-2S (509.8 -> 422.7) and HexN-UA-HexNAc-UA-2S (611.4 -> 524.1), associated with MPS-I/II and MPS-IIIA, respectively, were also included.…”

Section: Methodsmentioning

confidence: 99%

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A novel iPSC model reveals selective vulnerability of neurons in Multiple Sulfatase Deficiency

Pham,

Finoti,

Cassidy

et al. 2023

Preprint

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Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD is characterized by the functional deficiency of all sulfatase enzymes, leading to the storage of sulfated substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Patients with MSD experience severe neurological impairment, hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, and ichthyosis. Here, we generated a novel human model of MSD by reprogramming patient peripheral blood mononuclear cells to establish an MSD iPSC line (SUMF1p.A279V). We also generated an isogenic control iPSC line by correcting the pathogenic variant with CRISPR/Cas9 gene editing. We successfully differentiated these iPSC lines into neural progenitor cells (NPCs) and NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. Mature neuronal cells exhibited decreasedSUMF1gene expression, increased lysosomal stress, impaired neurite outgrowth and maturation, reduced sulfatase activities, and GAG accumulation. Interestingly, MSD iPSCs and NPCs did not exhibit as severe of phenotypes, suggesting that as neurons differentiate and mature, they become more vulnerable to loss ofSUMF1. In summary, we demonstrate that this human iPSC-derived neuronal model recapitulates the cellular and biochemical features of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.

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Glycosaminoglycans in mucopolysaccharidoses and other disorders

Khan,

Nidhi,

Leal

et al. 2024

Advances in Clinical Chemistry

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Endogenous, non-reducing end glycosaminoglycan biomarkers are superior to internal disaccharide glycosaminoglycan biomarkers for newborn screening of mucopolysaccharidoses and GM1 gangliosidosis

Cited by 7 publications

References 27 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

A novel iPSC model reveals selective vulnerability of neurons in Multiple Sulfatase Deficiency

Glycosaminoglycans in mucopolysaccharidoses and other disorders

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