Block or degrade? Balancing on- and off-target effects of antisense strategies against transcripts with expanded triplet repeats in DM1
Najoua El Boujnouni, M. Leontien van der Bent, Marieke Willemse, Peter A.C. ’t Hoen, Roland Brock, Derick G. Wansink
Abstract
foci. However, the repeat blocker was more effective in MBNL1 protein displacement and had superior efficiency in splicing correction at the tested dose of 100 nM. By comparison, on a transcriptome level, the blocking ASO had the fewest off-target effects. In particular, the off-target profile of the repeat gapmer asks for cautious consideration in further therapeutic development. Altogether, our study demonstrates the importance of evaluating both on-target and downstream effects of ASOs in a DM1 context, and provides guiding principles for safe and effective targeting of toxic transcripts.
Topics & Concepts
RNase HRNABiologyTrinucleotide repeat expansionRNA splicingTranscriptomeContext (archaeology)RNase POligonucleotideMyotonic dystrophyCell biologyMolecular biologyComputational biologyGeneticsGeneGene expressionAllelePaleontologyGenetic Neurodegenerative DiseasesCRISPR and Genetic EngineeringRNA Research and Splicing