I took some notes from the article and am happy to share them with anyone interested! The Problem: Antisense oligonucleotides (ASOs), which are designed to target and regulate specific genes, face two critical barriers limiting their therapeutic effectiveness: "endosomal entrapment” and “inefficient nuclear localization”. Only a small percentage of ASOs escape from endosomes to the cytosol and nucleus, preventing them from effectively modulating gene expression. The Potential Solution: Improving the …

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Antisense oligonucleotides (ASOs) are promising for targeting diseases by modulating gene expression, even for genes previously considered "undruggable." ASOs enter cells through endocytosis but face challenges as they often get trapped in endosomes, limiting their therapeutic effect. Strategies to enhance endosomal escape, including using endosomal escape agents and non-viral delivery vehicles, are critical to increase their effectiveness. Despite some success, only 1-2% of ASOs reach the target mRNA in the …

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1. Introduction: In the last 25 years, 18 oligonucleotide therapeutics have been approved for treating diseases like spinal muscular atrophy, Duchenne muscular dystrophy, and hereditary transthyretin-mediated amyloidosis. These therapies operate through different mechanisms, including antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi), and RNA aptamers. 2. Historical Background: Oligonucleotide therapeutics trace back to the 1950s and 1960s with early discoveries in DNA and RNA synthesis. Pioneers like Todd, Khorana, …

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