Do Chemically Modified Oligonucleotide Therapeutics Require Environmental Risk Assessment?

Abstract

Synthetic modified oligonucleotides (mONs) are a rapidly evolving class of nucleic acid–based therapeutics with an expected increase in market approval rates. mONs are designed to resist enzymatic degradation in patients, and their biological effects arise from chemical modifications and sequence-dependent phenomena comparable to those of biologically active genetic materials. These properties and the absence of experimental evidence on the occurrence and impact of mONs emitted into aquatic environments raise questions about the need for environmental risk assessment (ERA). Here, we evaluate (i) the chemical modifications proposed for mONs and found in approved therapeutics, (ii) pharmacological data on excretion to inform emission scenarios, (iii) analytical approaches for quantification of mONs in environmental matrices, (iv) anticipated distribution and transformation processes, and (v) potential (eco)toxicological effect profiles of mONs. We propose that focusing on chemical modifications allows for a more generalized approach to assessing mON exposure in engineered and natural aquatic systems. By contrast, the evaluation of effects requires case-by-case studies of chemical modifications and nucleotide sequences in the mON products. We suggest to address the need for ERAs by monitoring mONs in wastewater with newly developed analytical methods as well as experimental studies in laboratory model systems of processes that determine mON exposure and effects.