At the Heart of Genome Editing and Cardiovascular Diseases.

Abstract

Cardiovascular disease (CVD) is still the leading cause of death worldwide, but the knowledge and technologies for counteracting this disease may already be in our hands. Scientific advances over the past few years, such as the isolation and differentiation of induced pluripotent stem cells, and the development of gene-editing tools, have enabled us to model CVD, but more importantly, may represent tools for CVD early diagnosis, patient stratification, and treatment. The emergence of CRISPR/Cas9 technology has been envisioned as a simple and technically affordable tool for treating CVD. However, the biggest health burden associated with CVD cannot be addressed via CRISPR/Cas9-mediated gene correction, as most patients had atherosclerosis, and the most effective treatments for this condition currently involve changes in lifestyle. CRISPR/Cas9 technologies are also generally ineffective in treating congenital heart disorders, as we have not yet fully understood the exact role of multiple genes underlying these conditions.1 Moreover, for CRISPR/Cas9 to truly be a viable strategy against CVD, technical limitations of this technology (eg, mosaicism, off-target effects, low versatility in targeting different cell types, and random genome integration of CRISPR/Cas9 machinery) must be overcome. Unfortunately, these limitations are frequently being overlooked, evidenced for example by the initiation of several clinical trials, leading to the impression that a therapeutic solution is available. CRISPR/Cas9 is currently the most popular gene-editing tool, but there are other gene-editing technologies with additional capabilities. A more thorough understanding of DNA repair mechanisms is essential for further developing and translating to the clinic this gene-editing toolkit. DNA modifications can be generated by multiple site-directed nucleases, including the traditional meganucleases, ZFNs (zinc-finger nucleases), and TALENs (transcription activator-like effector nucleases), all of which generate double-strand breaks. Briefly, these nucleases recognize a specific DNA locus and cleave it. The DNA is then repaired by cellular machineries, with the …