INSPHERO, INC.:1302435 [25-000250]

Insphero, Inc., Brunswick ME

Investigators

Abstract

This requisition establishes a contract to evaluate the RNA expression in liver toxicity associated with the systemic administration of antisense oligonucleotides (ASOs) in the previously tested human, rat and mouse animal models. The project's phase one goal is to develop a predictive model of candidate ASO therapies' safety and acute toxicity. The National Center for Advancing Translational Sciences (NCATS) focuses on treating rare diseases. A significant emphasis of NCATS is the rapid development of effective therapies for patients diagnosed with these conditions. Although each condition is individually rare, cumulative rare diseases lead to considerable morbidity and mortality among the American population. NCATS is directly addressing this problem by discovering new technologies and other approaches, such as ASO therapies, that could significantly accelerate developing and deploying solutions that all translational researchers can use. The most significant bottleneck in terms of time and cost of ASO drug development is the animal toxicology experiments requested by the FDA. Having faster and cheaper screening methods for toxicology would address this critical issue. To facilitate the development of therapeutic ASOs, NCATS aims to develop streamlined and low-cost predictive toxicology assays for N=1 ASOs. These screening platforms rely on iPS cell cultures, organoids, and tissue bio-printing to predict the toxic side effects of ASOs and improve the safety pharmacology of this drug class. A parallel focus of our effort is to develop algorithms that predict toxicity, allowing toxic ASOs to be eliminated in the design phase. In this way, we aim to make developing disease-modifying therapies for rare diseases cheaper and faster by decreasing the burden of regulatory approval. In our previous efforts we used the 20-mer gapmer ASOs with phosphorothioate backbones and 2'-O-methoxyethyl-RNA (2'-MOE) modifications. We now want to validate the RNA expression of 7 of the ASOs in these cell-based screening organoids in animal models. This contract aims to provide sufficient and confirmatory in vivo data to the point that the FDA accepts cell-based in vitro data in place of conventional animal toxicology studies. NCATS is seeking technical support to evaluate the safety and acute liver toxicity of candidate ASOs by checking the gene expression. The results from these studies, in conjunction with existing cell-based assays, will help better predict the safety of future candidate ASOs intended for clinical use. Rare Diseases