Summary
Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules consisting of strands of 10–50 nucleotides. By targeted modulation of gene expression oligonucleotides provide the chance of targeting diseases at their molecular level. Within this novel emerging class of compounds oligonucleotide therapeutics are discriminated by their structure, function and mode of action. While antisense oligonucleotides, ribozymes and siRNAs suppress the expression of a protein by complementary hybridizing with their target mRNA, aptamers bind like antibodies to their target protein and thereby inhibit its function. Immunostimulatory oligonucleotides are due to sequence motifs within their nucleotide sequence able to trigger a therapeutic exploitable immune response. Currently, there are only two oligonucleotide therapeutics approved by the FDA, namely the antisense oligonucleotide Fomivirsen and the aptamer Macugen. In this review the mode of action of the diverse oligonucleotide therapeutics and their current status in clinical development will be discussed.
Zusammenfassung
Oligonukleotid Therapeutika sind kurzkettige DNA oder RNA Moleküle, die aus Einzeloder Doppelsträngen von 10–50 Nukleotiden bestehen. Sie ermöglichen gezielt die Expression von Genen zu beeinflussen, um Erkrankungen auf ihrer molekularen Ebene der Entstehung zu therapieren. Innerhalb dieser neuen Substanzklasse unterscheidet man je nach Struktur, Wirkungs- und Funktionsweise zwischen Antisense Oligonukleotiden, Ribozymen, siRNAs, Aptameren und immunstimulatorischen Oligonukleotiden. Während Antisense Oligonukleotide, Ribozyme und siRNAs gezielt die Expression eines Proteins durch komplementäre Basenpaarung an ihre Ziel-mRNA unterdrücken, binden Aptamere ähnlich wie Antikörper spezifisch an ihr Zielprotein und hemmen damit dessen Funktion. Immunstimulatorische Oligonukleotide sind aufgrund bestimmter in ihrer Nukleotidsequenz enthaltener "Sequenzmotive" in der Lage eine therapeutisch nutzbare Immunreaktion hervorzurufen. Derzeit sind mit dem Antisense Oligonukleotid Fomivirsen und dem Aptamer Macugen zwei Oligonukleotide als Arzneimittel zugelassen. Im vorliegenden Artikel sollen die Wirkungsmechanismen der unterschiedlichen Oligonukleotide dargestellt und eine Übersicht über den derzeitigen Entwicklungsstand als Therapeutika in den unterschiedlichen Indikationsbereichen gegeben werden.
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Wacheck, V. Oligonukleotid Therapeutika – eine neu entstehende Substanzklasse. Wien Med Wochenschr 156, 481–487 (2006). https://doi.org/10.1007/s10354-006-0331-4
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DOI: https://doi.org/10.1007/s10354-006-0331-4