Human-relevant disease models to accelerate the development of nucleic acid-based therapies and other advanced therapeutics.

Abstract

Advanced therapeutics, including programmable nucleic acid-based therapies (NATs), such as small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), CRISPR-Cas 9 editing systems, modified in vitro transcribed messenger RNAs (mRNAs) and Adeno-associated viruses (AAVs), have the potential to transform healthcare. However, while there have been considerable successes, there have also been notable clinical failures in early-stage human trials, which slowed down the progression of these therapeutic platforms. Multiple trials of NATs have been halted or discontinued, or approved products carry black box warnings as unforeseen or underestimated toxicities and poor efficacy have been observed in humans. There are a variety of reasons for failure of NATs, one of which is that many preclinical studies lack disease modelling in a human-relevant manner and, therefore, do not capture disease-specific effects on therapy tolerability and efficacy. This Perspective provides a short overview of why better human disease modelling is required to understand the potential therapeutic liabilities of NATs across modalities.