Targeted genome and epigenome editing for OA research and therapy

Abstract

Osteoarthritis (OA) represents a family of complex and chronic joint pathologies that have few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as OA [1]. These technologies enable precise targeting of DNA to allow activation, suppression, or editing of specific genes for disease modeling and therapeutic purposes. While genome-wide association studies (GWAS) and genomics have provided new leads on the genetic basis for various forms of OA, validation and characterization of the causal variants at these loci will be a key challenge that is necessary for identification of therapeutic targets (Fig. 1). With recent advances in gene editing and genome engineering technologies, functional validation of genetic variation of regulatory elements and coding sequences in human cell types has become feasible. The generation of cell lines with targeted editing of susceptibility variants in an isogenic background can be accomplished using newly developed tools for genome/epigenome editing. The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system has revolutionized the field of genome/epigenome editing by eliminating the need for protein engineering to obtain site specificity, thereby increasing accessibility to the platform. This presentation reviews some of the recent advances in CRISPR-Cas9-based genome editing, activation, inactivation, as well as epigenome editing. Applications of this method include: 1) development of cell-based systems for disease modeling as a basis for screening disease-modifying OA drugs (DMOADs); 2) targeted editing of the cellular genome for tissue engineering and regenerative medicine; 3) large-scale screening using libraries of CRISPR-based activators and inhibitors (CRISPRa/i) for identification/validation of genomic targets. Overall, there remains great opportunity to revolutionize the fields of OA research through application of these newly developed genome engineering tools.