SEMMs: Somatically Engineered Mouse Models. A New Tool for In Vivo Disease Modeling for Basic and Translational Research

Abstract

Most experimental oncology therapies fail during clinical development despite years of preclinical testing rationalizing their use. This begs the question of whether the current preclinical models used for evaluating oncology therapies adequately capture patient heterogeneity and response to therapy. Most of the preclinical work is based on xenograft models where tumor mis-location and the lack of the immune system represent a major limitation for the translatability of many observations from preclinical models to patients. Genetically engineered mouse models (GEMMs) hold great potential to recapitulate more accurately disease models but their cost and complexity have stymied their widespread adoption in discovery, early or late drug screening programs. Recent advancements in genome editing technology made possible by the discovery and development of the CRISPR/Cas9 system has opened the opportunity of generating disease-relevant animal models by direct mutation of somatic cell genomes in an organ or tissue compartment of interest. The advent of CRISPR/Cas9 has not only aided in the production of conventional GEMMs but has also enabled the bypassing of the construction of these costly strains. In this review, we describe the Somatically Engineered Mouse Models (SEMMs) as a new category of models where a specific oncogenic signature is introduced in somatic cells of an intended organ in a post-natal animal. In addition, SEMMs represent a novel platform to perform in vivo functional genomics studies, here defined as DIVoS (Direct In Vivo Screening).

Keywords: animal models; clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9-mediated genome editing; genetically engineered mouse models; mouse models; somatically engineered mouse models; translational research.

Figure 1

Schematic representation of different delivery modalities of the CRISPR/Cas9 system in vivo for SEMM generation (AAV, Adeno Associated Virus; Ads, Adenoviruses; LVs, Lentiviruses; RNPs, Ribonucleoproteins).

Figure 2

Representative workflow for SEMM generation and DIVoS design starting from CRISPR/Cas9 in vivo delivery. Targets identified with DIVoS are eventually validated with the generation of a SEMM (red dotted line).