Preclinical Safety Assessment of Therapeutic Oligonucleotides

Area of Science:

• Pharmacology and Toxicology
• Drug Discovery and Development

Background:

• Therapeutic oligonucleotide drugs (ONDs) have advanced significantly in chemistry and mechanistic understanding, leading to successful clinical applications.
• OND properties like pharmacokinetics, metabolism, and excretion (DMPK), and toxicity profiles vary based on OND class, chemistry, design, and delivery methods (e.g., lipid formulations, conjugation).
• ONDs with identical mechanisms, chemistry, and design exhibit consistent behavior, enabling extrapolation within OND classes.

Purpose of the Study:

• To summarize common toxicities associated with therapeutic oligonucleotides.
• To highlight advancements in mechanistic understanding of ONDs.
• To outline safety assessment strategies employed during OND drug discovery and development.

Main Methods:

• Review of common toxicities observed in therapeutic oligonucleotide drug development.
• Analysis of mechanistic understanding for various OND classes.
• Summary of safety assessment activities throughout the drug discovery and development pipeline.

Main Results:

• ONDs exhibit diverse DMPK and toxicity profiles influenced by their class, chemistry, design, and delivery systems.
• Consistent behavior within OND classes allows for inter-compound extrapolations.
• Established safety assessment protocols are crucial for therapeutic oligonucleotide development.

Conclusions:

• A comprehensive understanding of OND toxicity and mechanisms is vital for safe and effective drug development.
• Safety assessment strategies are critical for navigating the complexities of ONDs.
• Insights from therapeutic OND development can inform the use of oligonucleotides as research tools.