Development of LNA Gapmer Oligonucleotide-Based Therapy for ALS/FTD Caused by the C9orf72 Repeat Expansion

Novel Lipid-Oligonucleotide Conjugates Containing Long-Chain Sulfonyl Phosphoramidate Groups: Synthesis and Biological Properties

“…We have confirmed that LONs used in this study evinced low cytotoxicity. Calculated IC 50 of studied LONs fell within the 75 to 120 µM range, which was significantly higher than concentrations of antisense oligonucleotides targeting therapeutically relevant RNAs commonly used in vitro and in vivo: nanomolar concentrations [43][44][45][46] or <5 µM [47] or therapeutic doses of siRNAs and antisense oligonucleotides approved by FDA and EMA for clinical practice: for siRNAs 21 nmol/kg for Patisiran [48] and 153 nmol/kg for Givosiran [49]; for antisense oligonucleotides <5 µmoles/kg for Golodirsen [50], Volanesorsen [51] and Inotersen [52]. It is worth noting that the increase in hydrophobicity of the conjugates have no influence on their cytotoxicity (Figure 3).…”

The evolution and polymorphism of mono-amino acid repeats in androgen receptor and their regulatory role in health and disease

“…On RNA level one way of targeting these polymorphic regions is by antisense oligonucleotides (ASOs) and stabilized miRNA analogs, which inhibit the translation of mRNA, this represents a fast-developing modality of drug design for repeat-associated diseases like Huntington's disease (215)(216)(217), myotonic dystrophy type-1 (218-220) and amyotrophic lateral sclerosis (221)(222)(223). ASO stability and delivery have been ongoing problems, but now there is a growing number of new technologies for delivery, like liposomes, to mitigate these difficulties, which make them very attractive for targeting repeat-associated diseases (224).…”