Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa

Atanasova, Velina S.; Jiang, Qiujie; Prisco, Marco di; Gruber, Christina; Hofbauer, Josefina Piñón; Chen, Mei; Has, Cristina; Bruckner‐Tuderman, Leena; McGrath, John A.; Uitto, Jouni; South, Andrew P.

doi:10.1016/j.jid.2017.05.011

Cited by 73 publications

(79 citation statements)

References 48 publications

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“…Other substances such as PTC124 or amlexanox have become available that are known to induce read-through with lower risks of inadvertent effects than described for aminoglycosides [16, 29, 30]. Nevertheless, long-term clinical experiences with the use of gentamicin in infants exist, and a pilot study assessing the presence of functional laminin-332 in JEB patients with nonsense mutations after topical or intravenous gentamicin treatment (ClinicalTrials.gov, NCT03526159) started in June 2018.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin

Hammersen¹,

Neuner²,

Wild³

et al. 2019

Dermatology

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Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.

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Section: Discussionmentioning

confidence: 99%

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin

Hammersen¹,

Neuner²,

Wild³

et al. 2019

Dermatology

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“…if an exon were skipped, the resulting protein would contain all sequences found in the wild‐type C7 minus the 11–66 amino acids coded by the in‐frame exons . Considering read‐through of premature codon therapies, our data revealed three patients with in‐frame nonsense mutations who could potentially benefit from therapies such as topical gentamicin or systemic amlexanox …”

Section: Reportmentioning

confidence: 99%

“…Precision medicine relies on the ability to match a therapy with an appropriate genotype, as is the case for drugs that have the potential to read‐through premature termination codon (PTC) mutations or oligonucleotide‐mediated exon skipping. Proof‐of‐principle preclinical experiments for each of these emerging therapies in RDEB has been documented …”

Section: Reportmentioning

confidence: 99%

“…Currently, a number of different approaches to therapy are being developed, which require precise knowledge of an individual patient's mutation(s) . Some examples of these include DNA editing of induced pluripotent stem cells, targeted exon skipping, and read‐through of premature termination codon (PTC) mutations . To better inform strategies and to choose the most appropriate therapy in a given patient, a comprehensive analysis of genetic mutation is required.…”

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Seven novel COL7A1 mutations identified in patients with recessive dystrophic epidermolysis bullosa from Mexico

et al. 2018

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Recessive dystrophic epidermolysis bullosa (RDEB; OMIM #226600) is one of the most devastating subtypes of epidermolysis bullosa, a group of skin and mucous membrane blistering disorders often associated with extracutaneous manifestations. RDEB is caused by mutations in COL7A1, the gene encoding type VII collagen (C7), and to date over 700 different mutations in the 8835 nucleotides constituting the open reading frame or adjacent exon-intron boundaries of COL7A1 have been described. We used targeted next-generation sequencing to identify seven previously unreported mutations in a cohort of 17 Mexican patients who were diagnosed with RDEB based on clinical presentation and immunoepitope mapping. Our study expands the spectrum of mutations identified in this cohort, including those suitable for emerging therapies reliant on precise genotyping.

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“…Several substances that elicit premature termination codon (PTC) read‐through showed promising results in vitro for specific RDEB‐ and JEB‐associated mutations . The promise of PTC read‐through substances, which often fall into the small molecule category of drugs available for repurposing, is to express a previously absent protein.…”

Section: Clinical Researchmentioning

confidence: 99%

Epidermolysis bullosa: Advances in research and treatment

Prodinger

Reichelt

Bauer

et al. 2019

Experimental Dermatology

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Epidermolysis bullosa (EB) is the umbrella term for a group of rare inherited skin fragility disorders caused by mutations in at least 20 different genes. There is no cure for any of the subtypes of EB resulting from different mutations, and current therapy only focuses on the management of wounds and pain. Novel effective therapeutic approaches are therefore urgently required. Strategies include gene‐, protein‐ and cell‐based therapies. This review discusses molecular procedures currently under investigation at the EB House Austria, a designated Centre of Expertise implemented in the European Reference Network for Rare and Undiagnosed Skin Diseases. Current clinical research activities at the EB House Austria include newly developed candidate substances that have emerged out of our translational research initiatives as well as already commercially available medications that are applied in off‐licensed indications. Squamous cell carcinoma is the major cause of death in severe forms of EB. We are evaluating immunotherapy using an anti‐PD1 monoclonal antibody as a palliative treatment option for locally advanced or metastatic squamous cell carcinoma of the skin unresponsive to previous systemic therapy. In addition, we are evaluating topical calcipotriol and topical diacerein as potential agents to improve the healing of skin wounds in EBS patients. Finally, the review will highlight the recent advancements of gene therapy development for EB.

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Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa

Cited by 73 publications

References 48 publications

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin

Seven novel COL7A1 mutations identified in patients with recessive dystrophic epidermolysis bullosa from Mexico

Epidermolysis bullosa: Advances in research and treatment

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