ReviewPost screenSafety of antisense oligonucleotide and siRNA-based therapeutics

- Severe thrombocytopenia has been observed with a small number of antisense oligos.
- Peripheral neuropathy and mortality have been observed with an siRNA drug.
- We compared and contrasted the characteristics of these two classes of oligo drugs.
- A case study directly compares an ASO and an siRNA drug targeting the same gene.
- The goal is to understand factors contributing to ASO- and siRNA-induced toxicity.

Oligonucleotide-based therapy is an active area of drug development designed to treat a variety of gene-specific diseases. Two of the more promising platforms are the antisense oligonucleotides (ASOs) and short interfering RNAs (siRNAs), both of which are often directed against similar targets. In light of recent reports on clinical trials of severe thrombocytopenia with two different ASO drugs and increased peripheral neuropathy with an siRNA drug, we compared and contrasted the specific safety characteristics of these two classes of oligonucleotide therapeutic. The objectives were to assess factors that could contribute to the specific toxicities observed with these two classes of promising drugs, and get a better understanding of the potential mechanism(s) responsible for these rare, but serious, adverse events.