Antisense-Oligonukleotide I

Zusammenfassung

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.

Summary

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.

Schlüsselwörter

Antisense-Oligonukleotide - spinale Muskelatrophie (SMA) - Nusinersen - Amyotrophe Lateralsklerose (ALS) - Chorea Huntington

Keywords

Antisense oligonucleotides - spinal muscular atrophy (SMA) - nusinersen - amyotrophic lateral sclerosis (ALS) - Huntington`s disease (HD)

 

Interessenkonflikt

Heiko Graf: keine Interessenkonflikte. Diana Lehmann: keine Interessenkonflikte. Claudia Diana Wurster: Beratertätigkeit für die Firma Hoffmann-La Roche; Honorarvorträge für die Firma Biogen sowie Teilnahme an einem AdBoard Meeting der Firma Biogen. Albert Ludolph: Unterstützung für klinische Forschungsprojekte durch AB Science, Biogen Idec, Cytokinetics, GSK, Orion Pharam, Novartis, TauRx Therapeutics Ltd. und TEVA Pharmaceuticals. Honorare als Berater von Mitsubishi, Orion Pharma, Novartis, Teva sowie für lectures fees von Biogen und Ionis sowie als AdBoard-Mitglied von Biogen, Treeway, Hoffmann-La Roche und Novartis.

^* Dieser Artikel basiert auf (106)

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