Antisense-Oligonukleotide I
- 30 October 2018
- journal article
- Published by Georg Thieme Verlag KG in Nervenheilkunde
- Vol. 37 (11), 809-817
- https://doi.org/10.1055/s-0038-1675700
Abstract
Molekulargenetische Untersuchungen konnten die Pathomechanismen vieler neurodegenerativer Erkrankungen aufklären, jedoch standen lange Zeit keine krankheitsmodifizierenden Therapieoptionen zur Verfügung. Dies änderte sich seit der Einführung von sogenannten Antisense-Oligonukleotiden in die klinische Praxis. Im Jahr 2016 wurden erstmals Antisense-Oligonukleotide zur Behandlung der spinalen Muskelatrophie und der Muskeldystrophie Duchenne zugelassen. In der Entwicklung von Antisense-Oligonukleotiden waren Hürden zu überwinden und chemische Modifikationen notwendig, die deren Einsatz erst möglich machten. In diesem Artikel stellen wir Prinzipien dieser chemischen Modifikationen und Wirkmechanismen von Antisense-Oligonkuleotiden vor. Darüber hinaus geben wir einen Überblick über den aktuellen Stand der Wissenschaft zu verschiedenen Antisense-Oligonukleotiden und fokussieren dabei auf neuromuskuläre und neurodegenerative Erkrankungen wie die spinale Muskelatrophie, die Muskeldystrophie Duchenne, die myotone Dystrophie, Chorea Huntington und die Amyotrophe Lateralsklerose. Efforts in molecular biology and genetics provided considerable insights into the pathomechanisms of neurodegenerative disorders, but disease-modifying treatment options were scarce for decades. This changed since antisense oligonucleotide strategies could be translated from the bench to the clinic. In the year 2016, two antisense oligonucleotides were approved for the treatment of spinal muscular atrophy and for Duchenne muscular dystrophy. The development of antisense oligonucleotides was challenging and several chemical modifications were necessary to improve their drug-like properties and their successful introduction into clinical practice. In this review, we provide insights into the chemical modifications and the mechanism of action of antisense oligonucleotides. Moreover, we give an overview on several antisense oligonucleotides for the treatment of neurodegenerative or neuromuscular disorders and focus on spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy, Huntington´s disease and amyotrophic lateral sclerosis. * Dieser Artikel basiert auf (106)Keywords
This publication has 90 references indexed in Scilit:
- Oligonucleotide therapies for disorders of the nervous systemNature Biotechnology, 2017
- Pharmacology of Antisense DrugsAnnual Review of Pharmacology and Toxicology, 2017
- The delivery of therapeutic oligonucleotidesNucleic Acids Research, 2016
- Antisense oligonucleotides in therapy for neurodegenerative disordersAdvanced Drug Delivery Reviews, 2015
- Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotidesAdvanced Drug Delivery Reviews, 2015
- Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel TherapeuticsGene Regulation and Systems Biology, 2008
- Design of antisense oligonucleotides stabilized by locked nucleic acidsNucleic Acids Research, 2002
- Pathways of Degradation and Mechanism of Action of Antisense Oligonucleotides inXenopus laevisEmbryosAntisense Research and Development, 1991
- Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide.Proceedings of the National Academy of Sciences of the United States of America, 1978
- Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide.Proceedings of the National Academy of Sciences of the United States of America, 1978