ENPP1 inhibition as a therapeutic approach for later-onset hypophosphatasia Article Swipe
Sonoko Narisawa
,
Flávia Amadeu de Oliveira
,
Cíntia Kazuko Tokuhara
,
Elis Janaína Lira dos Santos
,
Elena Fonfria
,
Jennifer Batson
,
Zuling Cheng
,
A Houston
,
Brian L. Foster
,
José Luís Millán
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1093/jbmr/zjaf136
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1093/jbmr/zjaf136
Hypophosphatasia (HPP) is caused by loss-of-function mutations in the human ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP), whose deficiency results in the accumulation of the calcification inhibitor inorganic pyrophosphate (PPi), resulting in skeletal and dental hypomineralization. Enzyme replacement with mineral-targeted TNAP (asfotase alfa) improves skeletal mineralization but the almost daily injections of this biologic can lead to injection site reactions and discontinuation of treatment. Since PPi is produced by the enzymatic action of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) from adenosine triphosphate (ATP), we tested if ENPP1 could be a druggable target for the development of an alternative treatment for HPP, particularly for the non-lethal later-onset forms of HPP, where enzyme replacement is not currently approved. We orally administered 30 and 100 mg/kg/day of an ENPP1 inhibitor, REV102, to the AlplPrx1/− mouse model of late-onset HPP, for 105 days and confirmed target engagement, as plasma PPi concentrations were markedly reduced. X-ray, micro-CT, and bone morphometry indicated improvement in appendicular skeletal mineralization. This study suggests that the adult HPP phenotype could benefit from oral administration of ENPP1 inhibitors.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1093/jbmr/zjaf136
- https://academic.oup.com/jbmr/advance-article-pdf/doi/10.1093/jbmr/zjaf136/64519452/zjaf136.pdf
- OA Status
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- Cited By
- 2
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- 46
- OpenAlex ID
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All OpenAlex metadata
Raw OpenAlex JSON
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https://openalex.org/W4414853843Canonical identifier for this work in OpenAlex
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https://doi.org/10.1093/jbmr/zjaf136Digital Object Identifier
- Title
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ENPP1 inhibition as a therapeutic approach for later-onset hypophosphatasiaWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-10-05Full publication date if available
- Authors
-
Sonoko Narisawa, Flávia Amadeu de Oliveira, Cíntia Kazuko Tokuhara, Elis Janaína Lira dos Santos, Elena Fonfria, Jennifer Batson, Zuling Cheng, A Houston, Brian L. Foster, José Luís MillánList of authors in order
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https://doi.org/10.1093/jbmr/zjaf136Publisher landing page
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https://academic.oup.com/jbmr/advance-article-pdf/doi/10.1093/jbmr/zjaf136/64519452/zjaf136.pdfDirect link to full text PDF
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YesWhether a free full text is available
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hybridOpen access status per OpenAlex
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https://academic.oup.com/jbmr/advance-article-pdf/doi/10.1093/jbmr/zjaf136/64519452/zjaf136.pdfDirect OA link when available
- Cited by
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2Total citation count in OpenAlex
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2025: 2Per-year citation counts (last 5 years)
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46Number of works referenced by this work
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| referenced_works | https://openalex.org/W1997425710, https://openalex.org/W2998909574, https://openalex.org/W1872342032, https://openalex.org/W2058628090, https://openalex.org/W1999720487, https://openalex.org/W3179518022, https://openalex.org/W2172461241, https://openalex.org/W2280954766, https://openalex.org/W2102235351, https://openalex.org/W2208579015, https://openalex.org/W2763088472, https://openalex.org/W2066650336, https://openalex.org/W2002065866, https://openalex.org/W2071465976, https://openalex.org/W2037711685, https://openalex.org/W1984530261, https://openalex.org/W2141225628, https://openalex.org/W2738193737, https://openalex.org/W3088970141, https://openalex.org/W3164242868, https://openalex.org/W3169703262, https://openalex.org/W4406292263, https://openalex.org/W4312116028, https://openalex.org/W3093056287, https://openalex.org/W2767386149, https://openalex.org/W2039642869, https://openalex.org/W2623938296, https://openalex.org/W2885313290, https://openalex.org/W2972871973, https://openalex.org/W4283034667, https://openalex.org/W2513124599, https://openalex.org/W1494685702, https://openalex.org/W1493330691, https://openalex.org/W2069223770, https://openalex.org/W1990019150, https://openalex.org/W2082446278, https://openalex.org/W2503594136, https://openalex.org/W4289457218, https://openalex.org/W2048105979, https://openalex.org/W2163322218, https://openalex.org/W2016752237, https://openalex.org/W4286684970, https://openalex.org/W1993860509, https://openalex.org/W2988384695, https://openalex.org/W4404691800, https://openalex.org/W3004754137 |
| referenced_works_count | 46 |
| abstract_inverted_index.1 | 77 |
| abstract_inverted_index.a | 89 |
| abstract_inverted_index.30 | 119 |
| abstract_inverted_index.We | 116 |
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| abstract_inverted_index.105 | 137 |
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| abstract_inverted_index.PPi | 67, 145 |
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| abstract_inverted_index.site | 60 |
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| abstract_inverted_index.this | 54 |
| abstract_inverted_index.were | 147 |
| abstract_inverted_index.with | 40 |
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| abstract_inverted_index.ENPP1 | 86, 125, 175 |
| abstract_inverted_index.Since | 66 |
| abstract_inverted_index.adult | 166 |
| abstract_inverted_index.alfa) | 44 |
| abstract_inverted_index.could | 87, 169 |
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| abstract_inverted_index.Enzyme | 38 |
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| abstract_inverted_index.action | 73 |
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| abstract_inverted_index.tested | 84 |
| abstract_inverted_index.(ENPP1) | 78 |
| abstract_inverted_index.(TNAP), | 18 |
| abstract_inverted_index.REV102, | 127 |
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| abstract_inverted_index.discontinuation | 63 |
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| abstract_inverted_index.tissue-nonspecific | 15 |
| abstract_inverted_index.hypomineralization. | 37 |
| abstract_inverted_index.pyrophosphatase/phosphodiesterase | 76 |
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