Whole Family Systems Initiative

Oligonucleotide Toxicity (OligoTox) Open Data Challenge is sponsored by Department of Health and Human Services - National Institutes of Health. Background Oligonucleotides (“oligos”) are an emerging class of therapeutics most commonly used in the treatment of rare genetic diseases. As used here, the term “oligos” refers to short (typically 15-30 nucleotides in length) nucleic acids intended to be used as therapeutics to treat human diseases by modulating gene expression. Typically, oligo therapeutics contain chemical modifications in the phosphodiester backbone or sugar moiety to limit degradation by cellular nucleases. Examples of therapeutic oligos include anti-sense oligos (ASOs), siRNAs, and microRNA mimics. To date, there are 17 FDA-approved oligo therapeutics, and many more in clinical development, to treat rare genetic diseases, infectious diseases, and cancer. As with any new molecular entity used as a therapeutic, the consideration of toxicity is a critical requirement in assessing safety. Toxicity in oligo therapeutics may be sequence-dependent (e.g., hybridization to nucleic acids other than the intended target) or sequence-independent (e.g., binding to cellular proteins) and are primarily assessed through expensive and time-consuming animal studies. Notably, both the FDA ( FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs ) and NIH ( NIH to prioritize human-based research technologies | National Institutes of Health ) are focusing on new approach methodologies that can reduce animal testing in preclinical safety studies through practices such as use of in vitro human-based systems, in silico/computational modeling, and other innovative platforms that can collectively evaluate immunogenicity, toxicity, and pharmacodynamics in humans and improve the predictive relevance of preclinical drug testing. One possible strategy for assessing the toxicity of oligo therapeutics would be the use of in vitro human-based systems, including microphysiological systems (i.e., tissue chips, organs-on-a-chip) and 3-dimensional human organoids. NIH has already inves