Date: March 27, 2025
Time: 12pm EDT / 5pm CET
Title: Developing Oligonucleotides to Modulate HTT mRNA isoforms
Presentation Description:
Huntington’s Disease is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat tract within exon 1 of the Huntingtin gene. HTT1a, an isoform that results from a pre-mature polyadenylation event in the context of CAG expansions, is known to associate with mutant HTT mRNA and protein aggregates in HD mouse models, however, how HTT1a and mutant HTT interact to affect aggregates, and whether this interaction can be disrupted, is unknown. Here, using fully chemically modified oligonucleotides, we aim to develop tools to lower HTT1a expression, and use these methods of HTT1a lowering to better elucidate its role in HD biology.
Speaker:
Title: In Silico-Guided Selection of Target Sequences for RNase H1-Dependent Antisense Oligonucleotides
Presentation Description:
To reduce the number of antisense oligonucleotides (ASO) that are screened to find an effective one, in silico tools that guide target sequence selection are a promising option. In this work we combine and build upon existing tools to predict various ASO properties. These properties include accessibility and off-target analysis, an acute neurotolerability score, RNase H1 cleavage sequence preference, and ASO thermodynamic properties. ASO target sequences selected based on these factors have shown high knockdown levels in our hands. Although more data is needed to generalize our findings, these data suggest that the use of these in silico tools could improve the development of efficient RNase H1-dependent ASOs.
