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Cited by 27Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusGlycosylation and Glycoproteins Research

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

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Mosca, Rosario, van de Vlekkert, Diantha, Campos, Yvan, Fremuth, Leigh E., Cadaoas, Jaclyn, Koppaka, Vish, Kakkis, Emil, Tifft, Cynthia +7 more·2020·Journal of Clinical Medicine
DOI 10.3390/jcm9030695PMC PMC7141319
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Abstract

Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into the category of the so-called orphan diseases, for which no therapy is currently available. In this study we aimed to identify potential therapeutic modalities, targeting primarily patients affected by type I sialidosis, the attenuated form of the disease. We tested the beneficial effects of a recombinant protective protein/cathepsin A (PPCA), the natural chaperone of NEU1, as well as pharmacological and dietary compounds on the residual activity of mutant NEU1 in a cohort of patients’ primary fibroblasts. We observed a small, but consistent increase in NEU1 activity, following administration of all therapeutic agents in most of the fibroblasts tested. Interestingly, dietary supplementation of betaine, a natural amino acid derivative, in mouse models with residual NEU1 activity mimicking type I sialidosis, increased the levels of mutant NEU1 and resolved the oligosacchariduria. Overall these findings suggest that carefully balanced, unconventional dietary compounds in combination with conventional therapeutic approaches may prove to be beneficial for the treatment of sialidosis type I.

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  • Endogenous CTSA levels are rate-limiting for NEU1 activity.

    “This is in agreement with endogenous CTSA levels being rate-limiting for NEU1 activity (56, 81–82).”

    From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [82]

    Results §3.2 says the amount of PPCA (cathepsin A/CTSA) available to complex with NEU1 could be rate-limiting, and reports increased NEU1 activity after PPCA supplementation. The source supports a potential limiting role, but does not establish the unqualified claim that endogenous CTSA levels are rate-limiting for NEU1 activity. (LLM, conf=0.84)

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Authors
Mosca, R., van de Vlekkert, D., Campos, Y., Fremuth, L. E., Cadaoas, J., Koppaka, V., Kakkis, E., Tifft, C., Toro, C., Allievi, S., Gellera, C., Canafoglia, L., Visser, G., Annunziata, I., & d’Azzo, A.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
  • Ultragenyx Pharmaceutical (United States) (US)
  • National Institutes of Health (US)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • University Medical Center Utrecht (NL)
Corresponding author
d’Azzo, Alessandra
ORCID
Venue
Journal of Clinical Medicine
Publisher
MDPI AG
Published
2020-03-04
Volume
9
Issue
3
Pages
695
ISSN
2077-0383 (ISSN-L)
DOI
10.3390/jcm9030695
PMC
PMC7141319
OpenAlex
W3009788639
Cited by
27
References
2
Citations by year
2026: 4 · 2025: 2 · 2024: 10 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4
FWCI
1.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (GM104981)
  • Assisi Foundation of Memphis (NA)
  • American Lebanese Syrian Associated Charities (NA)
  • Ultragenyx Pharmaceuticals (NA)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
Keywords
NEU1, lysosomal storage disease, betaine, dietary supplementation, residual enzyme activity, fibroblasts, rare diseases

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