Hitching a Ride to Overcome Barriers: Nonclinical Safety Considerations for Bioconjugated Oligonucleotides

Area of Science:

• Pharmacology and Toxicology
• Biotechnology and Genetic Medicine

Background:

• Advances in nucleic acid-based therapeutics enable tissue-selective targeting and expanded applications of genetic medicines.
• Emerging modalities, such as antibody- and peptide-conjugated oligonucleotides, feature complex mechanisms of action.

Purpose of the Study:

• To review the current landscape of bioconjugated oligonucleotide (BCO) therapeutics.
• To summarize key safety liabilities associated with BCOs.
• To highlight nonclinical testing strategies for BCOs.

Main Methods:

• Review of current literature on bioconjugated oligonucleotide (BCO) therapeutics.
• Analysis of safety liabilities across protein scaffolds, linkers, and oligonucleotide payloads.
• Discussion of nonclinical approaches, including predictive safety assessments and in vivo toxicity studies.

Main Results:

• Bioconjugated oligonucleotide (BCO) therapeutics, including antibody- and peptide-conjugated oligonucleotides, represent a significant advancement in genetic medicine.
• Key safety liabilities identified across BCO components require careful evaluation.
• Tailored nonclinical testing strategies are essential for supporting clinical development.

Conclusions:

• Bioconjugated oligonucleotide (BCO) therapeutics necessitate specialized nonclinical evaluation strategies.
• Understanding component- and construct-driven toxicities is critical for safe clinical translation.
• Risk-based regulatory considerations for BCOs may differ from traditional therapeutics.