From mechanism to clinical translation: Understanding the off- and on-target toxicities of nucleic-acid-dependent therapeutics
Lead Research Organisation:
UNIVERSITY OF CAMBRIDGE
Abstract
Programmable nucleic acid-dependant therapies (NADTs) including siRNAs, antisense oligonucleotides (ASOs), CRISPR-cas 9 based editing systems, and modified in vitro transcribed mRNAs have the potential to transform healthcare. There have been considerable successes in NADT development, including the FDA/MHRA approved therapies Givosiran (siRNA) for acute hepatic porphyria and Nusinersen (ASO) for spinal muscular atrophy. However there have also been notable failures such as the ASOs Tominersin for Huntington’s Disease treatment and SRP-5051-201 for Duchenne’s Muscular Dystrophy. The emerging clinical toxicities which have resulted in withdrawal of NADTs from phase II/III clinical trials are hepato-, renal- and immuno-toxicity. There are 3 major factors which contribute to the general failures of NATDs namely, an incomplete understanding of mechanisms of toxicity associated with the on- and off-target binding of NADTs, insufficient predictability of preclinical cell/animal models and an inability to predict which chemistries/sequences trigger adverse outcome pathways (AOPs). The ability to address these challenges requires a broad range of expertise and multidisciplinary partnership between academia and industry. This proposed partnership between the MRC Toxicology Unit (MRC-TU/UoC), Astra Zeneca (AZ), Mary Lyon Centre (MLC) and CRUK Scotland Institute (CRUK-SI) brings together individuals with unique skill sets and our combined efforts, working closely in the precompetitive space, will provide solutions to these major challenges.
We will investigate ASOs, siRNAs and CRISPR-based editing systems. The nucleic acids that form a key part of these therapies and the AOPs that they trigger are conserved and by studying these 3 modalities we will gain essential information about the commonalities and distinctions of on- and off-target toxicities of NADTs. Four work-packages are proposed where the combined outputs will improve the safety profiles of NADTs. WP1: We will gain mechanistic understanding of the toxicities associated with NADTs, identify ways in which to improve their safety profiles, and generate new assays that predict adverse outcome. WP2: To develop novel, advanced humanised preclinical models to predict NADT toxicity in vitro. We will develop an advanced humanised model that is able to recapitulate kidney toxicity, since trial failure is frequently due to renal toxicity. WP3: To generate algorithms that are predictive of toxic NADTs to inform the safe-by-design agenda. To achieve this aim we will use multi-omic data sets provided by AZ in parallel with machine learning and AI. WP4: Translation of research outputs for stakeholder benefit. In this WP, the assays/tools (WP1) and the advanced humanised models (WP2) will be made available through the MLC which will run assays and screens, accessible and affordable to the wider biomedical community. The algorithms that predict safe ASO design (WP3) will be made available through open-access repositories. We will collaborate with regulatory bodies (MHRA, EMA, FDA) and contribute to new regulatory guidelines. Our approaches will be informed by clinical data obtained from patient cohorts, and interaction with patient interest groups, via UpNAT. Finally, the training provided in the partnership will build a diverse workforce with capacity and capability in safety science, ensuring the UK has a world-leading position in the development of advanced therapeutics for socioeconomic benefit.
We will investigate ASOs, siRNAs and CRISPR-based editing systems. The nucleic acids that form a key part of these therapies and the AOPs that they trigger are conserved and by studying these 3 modalities we will gain essential information about the commonalities and distinctions of on- and off-target toxicities of NADTs. Four work-packages are proposed where the combined outputs will improve the safety profiles of NADTs. WP1: We will gain mechanistic understanding of the toxicities associated with NADTs, identify ways in which to improve their safety profiles, and generate new assays that predict adverse outcome. WP2: To develop novel, advanced humanised preclinical models to predict NADT toxicity in vitro. We will develop an advanced humanised model that is able to recapitulate kidney toxicity, since trial failure is frequently due to renal toxicity. WP3: To generate algorithms that are predictive of toxic NADTs to inform the safe-by-design agenda. To achieve this aim we will use multi-omic data sets provided by AZ in parallel with machine learning and AI. WP4: Translation of research outputs for stakeholder benefit. In this WP, the assays/tools (WP1) and the advanced humanised models (WP2) will be made available through the MLC which will run assays and screens, accessible and affordable to the wider biomedical community. The algorithms that predict safe ASO design (WP3) will be made available through open-access repositories. We will collaborate with regulatory bodies (MHRA, EMA, FDA) and contribute to new regulatory guidelines. Our approaches will be informed by clinical data obtained from patient cohorts, and interaction with patient interest groups, via UpNAT. Finally, the training provided in the partnership will build a diverse workforce with capacity and capability in safety science, ensuring the UK has a world-leading position in the development of advanced therapeutics for socioeconomic benefit.