Preclinical Mouse Model Core

PROJECT SUMMARY PRECLINICAL MOUSE MODEL CORE Mouse models are a critical component to both understanding disease mechanisms and to serve as a key platform for preclinical testing of novel therapeutics. Although in vitro systems are very useful for screening a large number of gene editing designs, mice provide a tractable, mammalian system to clearly demonstrate

functional efficacy in vivo using a validated model of disease. These data are critical to support an IND for new treatments. The Preclinical Mouse Model Core is structured to provide centralized and scaled access to models, in vivo delivery expertise, and phenotyping capabilities to support the individual disease research projects for

this program, towards our goal of IND-enabling validation of genomic editing therapeutics. The Jackson Laboratory (JAX) houses the world's largest collection of mouse models of human disease, including all key models for this program. In addition, JAX has leveraged its expertise and scale to develop a broad set of services

that will serve to further support the needs of the individual projects in a cost-effective and high-throughput manner. This includes our Genetic Engineering Technology team who has, over the past 3-years, executed more than 2,200 CRISPR/Cas9-based projects of all levels of complexity for 400+ investigators around the world,

including the large-scale, high-throughput KOMP2 Center that has produced more than 1,000 gene knockouts. JAX has also built, outfitted, and opened a world-class mouse phenotyping clinic, the JAX Center for Biometric Analysis, which serves both individual faculty projects as well as larger-scale phenotyping needs. Critically, our

proposed Core will build on our current experience as a Small Animal Testing Center for the current Phase of the Somatic Cell Genome Editing consortium. This program leverages the capabilities of the JAX In Vivo Pharmacology Service, which provides comprehensive pre-clinical efficacy, tolerability, and pharmacokinetic

testing using mouse models. Over the past four years, our testing center has worked with 10 funded teams to provide second-site validation of novel genome editor delivery systems, independently evaluating their efficiency and specificity in reporter models. The Preclinical Mouse Models Core will take full advantage of this exceptional

infrastructure and expertise to achieve the goals of this U19 program. We propose these Specific Aims: 1) To provide key animal model resources to support the individual disease projects, including optimization of models and cohort generation; and 2) To execute delivery validation studies that build on proof-of-principle experiments

for each disease project.