Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa

被引:0
作者
Jover, Irene [1 ]
Ramos, Maria C. [2 ]
Escamez, Maria Jose [3 ,4 ,5 ,6 ]
Lozoya, Estrella [1 ]
Tormo, Jose R. [2 ]
de Prado-Verdun, Diana [6 ]
Mencia, Angeles [3 ,4 ,5 ,6 ]
Pont, Merce [1 ]
Puig, Carles [1 ]
Larraufie, Marie-Helene [1 ]
Gutierrez-Caballero, Cristina [1 ]
Reyes, Fernando [2 ]
Trincado, Juan Luis [1 ]
Garcia-Gonzalez, Vicente [1 ]
Cerrato, Rosario [1 ]
Andres, Miriam [1 ]
Crespo, Maribel [1 ]
Vicente, Francisca [2 ]
Godessart, Nuria [1 ]
Genilloud, Olga [2 ]
Larcher, Fernando [3 ,4 ,5 ,6 ]
Nueda, Arsenio [1 ]
机构
[1] Almirall SA, R&D Ctr, Laurea Miro 408-410, Barcelona 08980, Spain
[2] Fdn MEDINA, Parque Tecnol Salud, Ave Conocimiento 34, Granada 18016, Spain
[3] Univ Carlos III Madrid UC3M, Ctr Invest Energet, Ctr Invest Biomed Red Enfermedades Raras, Dept Bioingn Ingn Aerosp UC3M, Madrid, Spain
[4] U714 CIBER Enfermedades Raras CIBERER ISCIII, Ctr Invest Energet, Unidad Innovac Biomed, Madrid, Spain
[5] Fdn Jimenez Diaz IISFJD, Inst Invest Sanitaria, Madrid, Spain
[6] Ctr Invest Energet Medioambientales & Tecnol CIEMA, Madrid, Spain
来源
SCIENTIFIC REPORTS | 2024年 / 14卷 / 01期
关键词
PREMATURE TERMINATION CODONS; VII COLLAGEN; READ-THROUGH; IN-VITRO; GENE; EXPRESSION; AMINOGLYCOSIDES; PREVALENCE; ACTIVATION; KAEMPFEROL;
D O I
10.1038/s41598-024-67398-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age. A frequent class of mutations in RDEB is premature termination codons (PTC), which appear in homozygosity or compound heterozygosity with other mutations. RDEB has no cure and current therapies are mostly palliative. Using patient-derived keratinocytes and a library of 8273 small molecules and 20,160 microbial extracts evaluated in a phenotypic screening interrogating C7 levels, we identified three active chemical series. Two of these series had PTC readthrough activity, and one upregulated C7 mRNA, showing synergistic activity when combined with the reference readthrough molecule gentamicin. These compounds represent novel potential small molecule-based systemic strategies that could complement topical-based treatments for RDEB.
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页数:21
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共 70 条
  • [21] Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons
    Dabrowski, Maciej
    Bukowy-Bieryllo, Zuzanna
    Zietkiewicz, Ewa
    [J]. MOLECULAR MEDICINE, 2018, 24
  • [22] Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions
    De Gregorio, Cristian
    Catalan, Evelyng
    Garrido, Gabriel
    Morande, Pilar
    Bennett, Jimena Castillo
    Munoz, Catalina
    Cofre, Glenda
    Huang, Ya-Lin
    Cuadra, Barbara
    Murgas, Paola
    Calvo, Margarita
    Altermatt, Fernando
    Yubero, Maria Joao
    Palisson, Francis
    South, Andrew P. P.
    Ezquer, Marcelo
    Fuentes, Ignacia
    [J]. BIOLOGICAL RESEARCH, 2023, 56 (01)
  • [23] From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB)
    Eichstadt, Shaundra
    Tang, Jean Y.
    Solis, Daniel C.
    Siprashvili, Zurab
    Marinkovich, M. Peter
    Whitehead, Nedra
    Schu, Matthew
    Fang, Fang
    Erickson, Stephen W.
    Ritchey, Mary E.
    Colao, Max
    Spratt, Kaye
    Shaygan, Amir
    Ahn, Mark J.
    Sarin, Kavita Y.
    [J]. CLINICAL COSMETIC AND INVESTIGATIONAL DERMATOLOGY, 2019, 12 : 933 - 942
  • [24] Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry
    Fine, Jo-David
    [J]. JAMA DERMATOLOGY, 2016, 152 (11) : 1231 - 1238
  • [25] Nonsense-mediated mRNA decay in health and disease
    Frischmeyer, PA
    Dietz, HC
    [J]. HUMAN MOLECULAR GENETICS, 1999, 8 (10) : 1893 - 1900
  • [26] Premature termination codons in the DMD gene cause reduced local mRNA synthesis
    Garcia-Rodriguez, Raquel
    Hiller, Monika
    Jimenez-Gracia, Laura
    van der Pal, Zarah
    Balog, Judit
    Adamzek, Kevin
    Aartsma-Rus, Annemieke
    Spitali, Pietro
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2020, 117 (28) : 16456 - 16464
  • [27] Rescue of nonsense mutations by amlexanox in human cells
    Gonzalez-Hilarion, Sara
    Beghyn, Terence
    Jia, Jieshuang
    Debreuck, Nadege
    Berte, Gonzague
    Mamchaoui, Kamel
    Mouly, Vincent
    Gruenert, Dieter C.
    Deprez, Benoit
    Lejeune, Fabrice
    [J]. ORPHANET JOURNAL OF RARE DISEASES, 2012, 7
  • [28] Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis
    Graf, Martin R.
    Apte, Shruti
    Terzo, Esteban
    Padhye, Simran
    Shi, Shuhao
    Cox, Megan K.
    Clark, Roger B.
    Modur, Vijay
    Badarinarayana, Vasudeo
    [J]. JOURNAL OF MOLECULAR MEDICINE-JMM, 2023, 101 (04): : 375 - 385
  • [29] In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial
    Gurevich, Irina
    Agarwal, Pooja
    Zhang, PeiPei
    Dolorito, John A.
    Oliver, Stacie
    Liu, Henry
    Reitze, Nicholas
    Sarma, Nikhil
    Bagci, Isin Sinem
    Sridhar, Kunju
    Kakarla, Visesha
    Yenamandra, Vamsi K.
    O'Malley, Mark
    Prisco, Marco
    Tufa, Sara F.
    Keene, Douglas R.
    South, Andrew P.
    Krishnan, Suma M.
    Marinkovich, M. Peter
    [J]. NATURE MEDICINE, 2022, 28 (04) : 780 - +
  • [30] THE E7 GENE OF HUMAN PAPILLOMAVIRUS TYPE-16 IS SUFFICIENT FOR IMMORTALIZATION OF HUMAN EPITHELIAL-CELLS
    HALBERT, CL
    DEMERS, GW
    GALLOWAY, DA
    [J]. JOURNAL OF VIROLOGY, 1991, 65 (01) : 473 - 478