Emerging Gene-Editing Modalities for Osteoarthritis

Abstract

Osteoarthritis (OA) is a pathological degenerative condition of the joints that is widely prevalent worldwide, resulting in significant pain, disability, and impaired quality of life. The diverse etiology and pathogenesis of OA can explain the paucity of viable preventive and disease-modifying strategies to counter it. Advances in genome-editing techniques may improve disease-modifying solutions by addressing inherited predisposing risk factors and the activity of inflammatory modulators. Recent progress on technologies such as CRISPR/Cas9 and cell-based genome-editing therapies targeting the genetic and epigenetic alternations in OA offer promising avenues for early diagnosis and the development of personalized therapies. The purpose of this literature review was to concisely summarize the genome-editing options against chronic degenerative joint conditions such as OA with a focus on the more recently emerging modalities, especially CRISPR/Cas9. Future advancements in novel genome-editing therapies may improve the efficacy of such targeted treatments.

Keywords: CRISPR/Cas9; genome editing; miRNA; osteoarthritis.

Figure 1

Articular joint structure. (a) Bone and cartilage of a healthy tibiofemoral joint (b) Simulation of cartilage degeneration and bone spur formation in an osteoarthritic knee.

Figure 2

CRISPR/Cas mechanism. Trans-activating RNA (orange) with CRISPR RNA (blue) the guide RNA. The guide RNA assembles with the Cas9 protein to form the CRISPR complex. Using the guide RNA for specificity, the CRISPR complex binds to the target DNA. Transgenic DNA can be inserted using homology arm inserts.

Figure 3

Extracellular vesicle delivery of CRISPR/Cas9 in the treatment of OA. Inside a producer cell (left), engineered OA-targeted sgRNA transcription may occur. SgRNA combines with Cas9 to form CRISPR/Cas9 sgRNA complexes. CRISPR/Cas9 complexes load into extracellular vesicles with fluorescent tags containing a dimerization domain compatible with a dimerization domain in engineered CRISPR/Cas9 complexes. These fluorescent tags also contain targets for the target osteoarthritic cell (right). Loaded EVs attach to target cells and unload the CRISPR/Cas9 complexes, which are then transported to the nucleus to perform gene modification.