Abstract
During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated into successful clinical applications. Depending on the specific OND mechanism, chemistry, and design, the DMPK and toxicity properties can vary significantly between different OND classes and delivery approaches, the latterincluding lipid formulations or conjugation approaches to enhance productive OND uptake. At the same time, with the only difference between compounds being the nucleobase sequence, ONDs with same mechanism of action, chemistry, and design show relatively consistent behavior, allowing certain extrapolations between compounds within an OND class. This chapter provides a summary of the most common toxicities, the improved mechanistic understanding and the safety assessment activities performed for therapeutic oligonucleotides during the drug discovery and development process. Several of the considerations described for therapeutic applications should also be of value for the scientists mainly using oligonucleotides as research tools to explore various biological processes.
Highlights
Oligo Classes, Chemistries, and DesignsOligonucleotide drugs (OND) of different classes range from 10–12 up to 100 nucleotides in length, often with chemical modifications of the backbone and ribose sugar
For antisense oligonucleotides (ASOs) with a steric blocking activity, use of other chemistries resulting in neutral backbones like Phosphorodiamidate Morpholinos (PMO), Peptide nucleic acids (PNA) and tricyclo-DNA is possible and quite common [9–13]
This chapter will focus on safety assessment of the hybridization dependent PS backbone ASOs and short interfering RNAs (siRNAs)
Summary
Oligonucleotide drugs (OND) of different classes range from 10–12 up to 100 nucleotides in length, often with chemical modifications of the backbone and ribose sugar. Rather than binding to RNA, the threedimensional structure of folded RNA of a given sequence is combined with chemical modifications to achieve specific binding to proteins. Other therapeutic approaches such as mRNA therapy and the guide RNA in various gene editing approaches (e.g., CRISPR/ CAS9) utilize nucleotides and but are commonly not classified as ONDs. This chapter will focus on safety assessment of the hybridization dependent PS backbone ASOs and siRNA
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