The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.
Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246
Open accessAbstract
P63 is a major transcription factor regulating skin development and homeostasis. It controls many genes involved in cell proliferation, adhesion, and early differentiation. P63 is mutated in several rare syndromes called p63-related ectodermal dysplasia syndromes (ED). The main forms are EEC and AEC syndromes due to p63 missense mutations on the DBD and SAM domains, respectively. ED patients display many developmental defects, including ectrodactyly, clef/lip palate, and ectodermal dysplasia, while AEC patients suffer from severe skin erosions that not always heal. We have previously showed that ED-derived iPSC display altered epidermal commitment. P63 belongs to the p53 gene family sharing similar structural domains. We found that ED-iPSC epidermal commitment can be rescued by a p53-reactivating compounds called PRIMA-1 MET, also named APR-246 and currently used in anticancer clinical trials. Here, we established primary epidermal culture from two AEC children (S.F. and Y.M.) suffering from persistent skin erosions at age of 9 and 15, respectively. These patients carry missense mutations on the SAM domain (I576T and I537T). We found that primary keratinocytes (KCs) isolated from these AEC patients underwent altered epidermal differentiation that was rescued by PRIMA-1 MET treatment. It prompted us to formulate the compound onto a cream that was topically applied on the right hand of one patient and on the scalp of the second patient. In both cases, the daily treatment allowed re-epithelialization of the eroded skin and a drastic loss of pain after few weeks, improving quality of life. Normally, mutant p63 exerts a dominant-negative effect, mainly through the formation of aggregate with WT p63 and p73. PRIMA-1 MET did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1 MET targets cell differentiation and not p63 activity directly. In conclusion, we propose that repurposing of the antitumoral PRIMA-1 MET compound could become a general treatment of AEC skin erosions.
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Topical PRIMA-1MET, a p53 reactivator, has been shown to augment epidermal differentiation and improve wound healing in patients with AEC syndrome.
“Apart from this, PRIMA-1MET, a p53 reactivator, when applied topically, has been shown to augment epidermal differentiation and improve wound healing in patients with AEC syndrome.[57]”
From Ectodermal Dysplasia – An Overview and Update (2024) · cites this paper as [57]
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Cites
p63 Is Essential for the Proliferative Potential of Stem Cells in Stratified Epithelia
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Maintaining epithelial stemness with p63
Melino, G., Memmi, E. M., Pelicci, P. G., & Bernassola, F. (2015) · Science Signaling · doi:10.1126/scisignal.aaa1033 · Cited by 139
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Research works printed but not linked: 13
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- Shalom-Feuerstein, R. et al. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc. Natl Acad. Sci. USA 110, 2152–2156 (2013). · DOI
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Ectodermal dysplasias: New perspectives on the treatment of so far immedicable genetic disorders
Schneider, H. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1000744 · Cited by 26
Ectodermal Dysplasia – An Overview and Update
Dev, A., Malhi, K., & Mahajan, R. (2024) · Indian Dermatology Online Journal · doi:10.4103/idoj.idoj_599_23 · Cited by 19
“[57]”
Metadata
- Authors
- Aberdam, E., Roux, L. N., Secrétan, P.-H., Boralevi, F., Schlatter, J., Morice-Picard, F., Sol, S., Bodemer, C., Missero, C., Cisternino, S., Aberdam, D., & Hadj-Rabia, S.
- Affiliations
- Inserm (FR)
- Université Paris-Sud (FR)
- Hôpital Necker-Enfants Malades (FR)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- Corresponding author
- Aberdam, Daniel
- Hadj-Rabia, Smail
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2020-01-16
- Volume
- 11
- Issue
- 1
- Pages
- 30-30
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6965199
- OpenAlex
- W2999588368
- Cited by
- 26
- References
- 2
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 4
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fondazione Telethon (GGP16235)
- Topics
- Health Sciences › Medicine › Dermatology › Genetic and rare skin diseases.
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Health Sciences › Dentistry › General Dentistry › dental development and anomalies
- Keywords
- aplasia cutis congenita, PRIMA-1MET, APR-246, p53 reactivation, epidermal differentiation, keratinocytes, skin erosion, topical cream, drug repurposing, re-epithelialization, p73
- MeSH terms
- Administration, Topical, Cell Differentiation, Ectodermal Dysplasia, Epidermis, Genotype, Humans, Phenotype, Quinuclidines, Transcription Factors, Keratinocytes, Tumor Suppressor Proteins, Protein Aggregates
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