ArticleAmerican journal of human genetics2014
Antisense oligonucleotide-based therapy in human erythropoietic protoporphyria.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- A splice-switching antisense oligonucleotide approach for pediatric genetic epilepsies.bioRxiv : the preprint server for biology · 2025Article
- The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria.The Journal of clinical investigation · 2025Article
- Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Case report: Xeroderma pigmentosum Group A with erythropoietic protoporphyria in a young Chinese patient.Frontiers in endocrinology · 2024Article
- Peptide Conjugates of a 2'-ACS omega · 2023Article
- Protoporphyrin IX-induced phototoxicity: Mechanisms and therapeutics.Pharmacology & therapeutics · 2023Review
- Article
- [Advances in the diagnosis and treatment of porphyria-related hepatic manifestations].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2022Article
- Heme Biosynthetic Gene Expression Analysis With dPCR in Erythropoietic Protoporphyria Patients.Frontiers in physiology · 2022Article
- Article
- Porphyrias in the Age of Targeted Therapies.Diagnostics (Basel, Switzerland) · 2021Review
- Erythropoietic protoporphyria: time to prodrome, the warning signal to exit sun exposure without pain-a patient-reported outcome efficacy measure.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Opportunities and challenges for antisense oligonucleotide therapies.Journal of inherited metabolic disease · 2021Review
- Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of erythropoietic protoporphyria.Nucleic acids research · 2020Article
- The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements.Journal of clinical medicine · 2019Article
- Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria.American journal of human genetics · 2019Article
- Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury.Cellular and molecular gastroenterology and hepatology · 2019Review
- Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice.Disease models & mechanisms · 2017Article
- [Advances in genes mutation and pathophysiology of congenital sideroblastic anemia].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2016Article
- [Erythropoietic protoporphyria : Clinical manifestations, diagnosis and new therapeutic possibilities].Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete · 2016Review
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Authors and funding
18 authors at 9 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
In 90% of people with erythropoietic protoporphyria (EPP), the disease results from the inheritance of a common hypomorphic FECH allele, encoding ferrochelatase, in trans to a private deleterious FECH mutation. The activity of the resulting FECH enzyme falls below the critical threshold of 35%, leading to the accumulation of free protoporphyrin IX (PPIX) in bone marrow erythroblasts and in red cells. The mechanism of low expression involves a biallelic polymorphism (c.315-48T>C) localized in intron 3. The 315-48C allele increases usage of the 3' cryptic splice site between exons 3 and 4, resulting in the transcription of an unstable mRNA with a premature stop codon, reducing the abundance of wild-type FECH mRNA, and finally reducing FECH activity. Through a candidate-sequence approach and an antisense-oligonucleotide-tiling method, we identified a sequence that, when targeted by an antisense oligonucleotide (ASO-V1), prevented usage of the cryptic splice site. In lymphoblastoid cell lines derived from symptomatic EPP subjects, transfection of ASO-V1 reduced the usage of the cryptic splice site and efficiently redirected the splicing of intron 3 toward the physiological acceptor site, thereby increasing the amount of functional FECH mRNA. Moreover, the administration of ASO-V1 into developing human erythroblasts from an overtly EPP subject markedly increased the production of WT FECH mRNA and reduced the accumulation of PPIX to a level similar to that measured in asymptomatic EPP subjects. Thus, EPP is a paradigmatic Mendelian disease in which the in vivo correction of a common single splicing defect would improve the condition of most affected individuals.
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