Investigating the Impact of Metabolic Disease States on the Pharmacodynamics and Toxicity of FDA-Approved Antisense Oligonucleotides Using an Integrated Liver-Kidney Model

About This Grant

Anti-sense oligonucleotide (ASO) drugs have shown great potential in the treatment of human diseases. However, the lack of therapeutic efficacy and intolerance of adverse drug reactions (ADRs) and toxicity have led to the termination of numerous ASO candidates in the development pipelines, as well as the discontinuation from the market after approval by the FDA. Hepatotoxicity and nephrotoxicity are two major concerns for the FDA-approved ASO drugs in the market as well as development of new ASO-based therapies. Significant knowledge gaps still exist which prevent us from better understanding the lack of effectiveness and existence of ADRs and toxicity. One of these gaps lies in how an ASO drug goes through absorption, distribution, metabolism, and excretion (ADME) in its target organs and cells. Both in vitro cellular models and in vivo animal models have been used to assess ADME and toxicity of ASO drugs; however, they have numerous limitations. While cellular models lack human complexity, animal models lack human-specificity. Microphysiological systems (MPSs) may provide a solution to overcome this unmet need by providing human specificity and complexity as an in vitro platform. Here, we propose using the Javelin Liver Tissue Chip Plus (LTC+) platform, which integrates human liver and kidney MPSs, to study distribution, metabolism, excretion, and toxicity profiles (hepato- and nephrotoxicity) of four FDA-approved ASO drugs.