Read-Through for Nonsense Mutations in Type XVII Collagen‒Deficient Junctional Epidermolysis Bullosa

Has, Cristina; Sayar, Saliha Beyza; Zheng, Shuangshuang; Chacón-Solano, Esteban; Condrat, Irina; Yadav, Ayushi; Roberge, Michel; Laguzzi, Fernando Larcher

doi:10.1016/j.jid.2021.09.018

Cited by 5 publications

(4 citation statements)

References 19 publications

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Section: Aminog Lycos Ide Antib Iotic Smentioning

confidence: 99%

“…Paromomycin has been tested, among other substances, for its potency to induce SCR in keratinocytes derived from junctional EB patients (harbouring COL17A1 nonsense mutations with no detectable COL17 expression) in a study by Has et al 52 . Results showed the highest production of functional type XVII collagen in a dose‐dependent manner for the p.W464* (NM_000494.4:c.1391G > A; NP_000485.3:p.Trp464Ter) mutation in response to treatment with the aminoglycoside antibiotics gentamicin, paromomycin and G418 when analysed by immunoblot in vitro.…”

Section: Aminoglycoside Antibioticsmentioning

confidence: 99%

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Stop codon readthrough as a treatment option for epidermolysis bullosa—Where we are and where we are going

Zandanell,

Wießner,

Bauer

et al. 2024

Experimental Dermatology

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In the context of rare genetic diseases caused by nonsense mutations, the concept of induced stop codon readthrough (SCR) represents an attractive avenue in the ongoing search for improved treatment options. Epidermolysis bullosa (EB)—exemplary for this group of diseases—describes a diverse group of rare, blistering genodermatoses. Characterized by extreme skin fragility upon minor mechanical trauma, the most severe forms often result from nonsense mutations that lead to premature translation termination and loss of function of essential proteins at the dermo‐epidermal junction. Since no curative interventions are currently available, medical care is mainly limited to alleviating symptoms and preventing complications. Complementary to attempts of gene, cell and protein therapy in EB, SCR represents a promising medical alternative. While gentamicin has already been examined in several clinical trials involving EB, other potent SCR inducers, such as ataluren, may also show promise in treating the hitherto non‐curative disease. In addition to the extensively studied aminoglycosides and their derivatives, several other substance classes—non‐aminoglycoside antibiotics and non‐aminoglycoside compounds—are currently under investigation. The extensive data gathered in numerous in vitro experiments and the perspectives they reveal in the clinical setting will be discussed in this review.

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Section: Aminog Lycos Ide Antib Iotic Smentioning

confidence: 99%

Section: Aminoglycoside Antibioticsmentioning

confidence: 99%

Stop codon readthrough as a treatment option for epidermolysis bullosa—Where we are and where we are going

Zandanell,

Wießner,

Bauer

et al. 2024

Experimental Dermatology

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“…The response to aminoglycosides gentamicin, paromomycin and G418 depended on the nature of the stop codon. Although some mutations (e.g., p.W464*) displayed a robust response, other mutations (i.e., p.R1226* and p.S140*) were completely refractory to aminoglycoside treatment [ 136 ].…”

Section: Nonsense Suppression In the Context Of Rare Genetic Diseases...mentioning

confidence: 99%

Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond

Wagner

Wießner

Friedrich

et al. 2023

IJMS

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Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.

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“…The incorporation of an amino acid into the nascent polypeptide chain at the site of PTC allows translation elongation and continuation of full-length protein synthesis [11][12][13][14]. Aminoglycoside-mediated PTC readthrough therapy has been extensively investigated in various rare genetic disorders such as cystic fibrosis (CF) [15], Duchenne muscular dystrophy (DMD) [16,17], Alport syndrome [18], and Epidermolysis Bullosa [19] as well as cancers [20][21][22]. In line with our previous findings, we have demonstrated that aminoglycosides G418 and gentamicin can induce readthrough of PTCs in the RTT-nonsense mutations [23,24].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome

Wong

Wegener

Baradaran‐Heravi

et al. 2023

IJMS

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Rett syndrome (RTT), a severe X-linked neurodevelopmental disorder, is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). Over 35% RTT patients carry nonsense mutation in MECP2, making it a suitable candidate disease for nonsense suppression therapy. In our previous study, gentamicin was found to induce readthrough of MECP2 nonsense mutations with modest efficiency. Given the recent discovery of readthrough enhancers, CDX compounds, we herein evaluated the potentiation effect of CDX5-1, CDX5-288, and CDX6-180 on gentamicin-mediated readthrough efficiency in transfected HeLa cell lines bearing the four most common MECP2 nonsense mutations. We showed that all three CDX compounds potentiated gentamicin-mediated readthrough and increased full-length MeCP2 protein levels in cells expressing the R168X, R255X, R270X, and R294X nonsense mutations. Among all three CDX compounds, CDX5-288 was the most potent enhancer and enabled the use of reduced doses of gentamicin, thus mitigating the toxicity. Furthermore, we successfully demonstrated the upregulation of full-length Mecp2 protein expression in fibroblasts derived from Mecp2R255X/Y mice through combinatorial treatment. Taken together, findings demonstrate the feasibility of this combinatorial approach to nonsense suppression therapy for a subset of RTT patients.

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Read-Through for Nonsense Mutations in Type XVII Collagen‒Deficient Junctional Epidermolysis Bullosa

Cited by 5 publications

References 19 publications

Stop codon readthrough as a treatment option for epidermolysis bullosa—Where we are and where we are going

Stop codon readthrough as a treatment option for epidermolysis bullosa—Where we are and where we are going

Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond

Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome

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