Local dystrophin restoration with antisense oligonucleotide PRO051
| Autor: | Edna H. Venneker, Jan J.G.M. Verschuuren, Anneke A.M. Janson, Ieke B. Ginjaar, Gert-Jan B. van Ommen, Nathalie Goemans, Annemieke Aartsma-Rus, Johan T. den Dunnen, Klaas Koop, Mattie Bremmer-Bout, Anneke J. van der Kooi, Peter F. Ekhart, Judith C.T. van Deutekom, Wendy S. Frankhuizen, Sjef J. de Kimpe, Gerard Johannes Platenburg |
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| Přispěvatelé: | ANS - Amsterdam Neuroscience, Neurology |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Male
musculoskeletal diseases medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Adolescent Transcription Genetic RNA Splicing Oligonucleotides Eteplirsen Injections Intramuscular Dystrophin Exon Tibialis anterior muscle Internal medicine medicine Humans RNA Messenger Muscular dystrophy Child Drisapersen Sequence Deletion biology business.industry General Medicine Exons Oligonucleotides Antisense medicine.disease Molecular biology Exon skipping Muscular Dystrophy Duchenne Endocrinology Drug Design RNA splicing biology.protein business |
| Zdroj: | New England journal of medicine, 357(26), 2677-2686. Massachussetts Medical Society |
| ISSN: | 0028-4793 |
| Popis: | Background: Duchenne's muscular dystrophy is associated with severe, progressive muscle weakness and typically leads to death between the ages of 20 and 35 years. By inducing specific exon skipping during messenger RNA (mRNA) splicing, antisense compounds were recently shown to correct the open reading frame of the DMD gene and thus to restore dystrophin expression in vitro and in animal models in vivo. We explored the safety, adverse-event profile, and local dystrophin-restoring effect of a single, intramuscular dose of an antisense oligonucleotide, PRO051, in patients with this disease. Methods: Four patients, who were selected on the basis of their mutational status, muscle condition, and positive exon-skipping response to PRO051 in vitro, received a dose of 0.8 mg of PRO051 injected into the tibialis anterior muscle. A biopsy was performed 28 days later. Safety measures, composition of mRNA, and dystrophin expression were assessed. Results: PRO051 injection was not associated with clinically apparent adverse events. Each patient showed specific skipping of exon 51 and sarcolemmal dystrophin in 64 to 97% of myofibers. The amount of dystrophin in total protein extracts ranged from 3 to 12% of that found in the control specimen and from 17 to 35% of that of the control specimen in the quantitative ratio of dystrophin to laminin alpha 2. Conclusions: Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible |
| Databáze: | OpenAIRE |
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