Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis
Open accessAbstract
Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mice injected with intermediate or high dose of rAAV showed normal PPCA expression in the choroid plexus, accompanied by clearance of lysosomal storage.
“Remarkably, mice injected with intermediate or high dose of rAAV showed normal PPCA expression in the choroid plexus, accompanied by clearance of lysosomal storage 60.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
The Results report that choroid-plexus vacuolization was fully reversed in intermediate- and high-dose-treated mice. But the Discussion says PPCA was not detectable in brain tissue or specific brain regions; it proposes that circulating PPCA below the detection limit was taken up by choroid-plexus cells. The claim of normal PPCA expression there is not supported. (LLM, conf=0.91)
Experimental — accuracy not yet measuredIncreased expression of PPCA was paralleled by rescue of endogenous activity of Neu1 and normalization of urinary oligosaccharides.
“Increased expression of PPCA was paralleled by rescue of the endogenous activity of Neu1 and normalization of urinary oligosaccharides.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
The sections on PPCA expression and CA/Neu1 activity report increased PPCA expression in treated mice and restored endogenous Neu1 activity. The urinary-oligosaccharide results report clearance of abnormal high-molecular-weight oligosaccharides in most treated mice, but some low-dose-treated males still had trace amounts, so normalization was not complete across all treated mice. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRegardless of viral dose used, rAAV-treated Ppca−/− mice appeared indistinguishable from WT mice; they had normal fur, coordination and gait, moved actively and were no longer edematous.
“Regardless of the viral dose used, treated mice appeared indistinguishable from WT mice; they had normal fur, coordination and gait, moved actively and were no longer edematous.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
Treated mice showed reversal of their infertility because they were able to produce normal size litters.
“Interestingly, treated mice showed reversal of their infertility because they were able to produce normal size litters.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
No adverse side effects have been identified and no difference in heart and lung morphology has been observed.
“No adverse side effects have been identified and no difference in heart and lung morphology has been observed.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
The rescue of PPCA and Neu1 activities resulted in a dramatic improvement of tissue architecture in all visceral organs tested.
“The rescue of PPCA and Neu1 activities resulted in a dramatic improvement of tissue architecture in all visceral organs tested.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
Levels of PPCA expression in treated mice correlated well with the dose of administered virus.
“Immunohistochemical and biochemical analysis of tissues showed that the levels of PPCA expression in treated mice correlated well with the dose of administered virus.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nathwani, A. C., Rosales, C., McIntosh, J., Rastegarlari, G., Nathwani, D., Raj, D., Nawathe, S., Waddington, S. N., Bronson, R., Jackson, S., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2010.274 · Cited by 345 · see citing works
Self-citationAllay, J. A., Sleep, S., Long, S., Tillman, D. M., Clark, R., Carney, G., Fagone, P., McIntosh, J. H., Nienhuis, A. W., Davidoff, A. M., et al. (2011) · Human Gene Therapy · doi:10.1089/hum.2010.202 · Cited by 152 · see citing works
Self-citationHermo, L., Korah, N., Gregory, M., Liu, L. Y., Cyr, D. G., D'Azzo, A., & Smith, C. E. (2007) · Journal of Andrology · doi:10.2164/jandrol.107.002980 · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- d'Azzo, A, Andria, G, Strisciuglio, P and Galjaard, H (2001). Galactosialidosis. In: Scriver, C, Beaudet, A, Sly, W and Valle D (eds). The Metabolic and Molecular Bases of Inherited Disease, 8th edn., vol. 3. McGraw-Hill: New York. pp. 3811-3826.
- Galjaard, H (1980). Genetic Metabolic Disease: Diagnosis and Prenatal Analysis. Elsevier Science Publishers B.V.: Amsterdam.
Cited by
Sorted by citations
Annunziata, I., Patterson, A., Helton, D., Hu, H., Moshiach, S., Gomero, E., Nixon, R., & d’Azzo, A. (2013) · Nature Communications · doi:10.1038/ncomms3734 · Cited by 146 · see citing works
Self-citationGalactosialidosis: historic aspects and overview of investigated and emerging treatment options
Annunziata, I., & d’Azzo, A. (2017) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2016.1266933 · Cited by 50 · see citing works
Self-citationStructure of the immunoregulatory sialidase NEU1
Gorelik, A., Illes, K., Mazhab-Jafari, M. T., & Nagar, B. (2023) · Science Advances · doi:10.1126/sciadv.adf8169 · Cited by 36 · see citing works
- Authors
- Hu, H., Gomero, E., Bonten, E., Gray, J. T., Allay, J., Wu, Y., Wu, J., Calabrese, C., Nienhuis, A., & d'Azzo, A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Nienhuis, Arthur
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 20
- Issue
- 2
- Pages
- 267-274
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3277225
- OpenAlex
- W2054904603
- Cited by
- 37
- References
- 3
- Citations by year
- 2026: 2 · 2024: 6 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 1
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Assisi Foundation of Memphis
- St. Jude Children's Research Hospital
- American Lebanese Syrian Associated Charities
- National Institutes of Health (1r13gm060905-01, DK-52025)
- National Institute of General Medical Sciences (GM60905)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-52025, Z01DK052025, R01DK052025, R01DK095169)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- galactosialidosis, lysosomal storage disease, PpcA, gene therapy, dose-finding, liver-specific promoter, cross-correction, infertility, systemic disease
- MeSH terms
- Dependovirus, Animals, Disease Models, Animal, Enzyme Activation, Female, Fertility, Genetic Vectors, Humans, Kidney, Liver, Male, Neuraminidase, Oligosaccharides, Organ Size, Spleen, Genetic Therapy, Gene Expression, Lysosomal Storage Diseases, Mice, Knockout, Cathepsin A, Mice, Viral Tropism
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
