Therapeutic Genome Editing in Cardiovascular Diseases

Abstract

A variety of genetic cardiovascular diseases may one day be curable using gene editing technology. Germline genome editing and correction promises to permanently remove monogenic cardiovascular disorders from the offspring and subsequent generations of affected families. Although technically feasible and likely to be ready for implementation in humans in the near future, this approach remains ethically controversial. Although currently beset by several technical challenges, and not yet past small animal models, somatic genome editing may also be useful for a variety of cardiovascular disorders. It potentially avoids ethical concerns about permanent editing of the germline and allows treatment of already diseased individuals. If technical challenges of Cas9-gRNA delivery (viral vector immune response, nonviral vector delivery) can be worked out, then CRISPR-Cas9 may have a significant place in the treatment of a wide variety of disorders in which partial or complete gene knockout is desired. However, CRISPR may not work for gene correction in the human heart because of low rates of homology directed repair. Off-target effects also remain a concern, although, thus far, small animal studies have been reassuring. Some of the therapies mentioned in this review may be ready for small clinical trials in the near future.

Keywords: CRISPR; DMD, Duchenne muscular dystrophy; DSB, double-stranded break; HCM, hypertrophic cardiomyopathy; NHEJ, nonhomologous end-joining; gene editing; germline gene correction.

Graphical abstract

Central Illustration

The Different Genome Editing Approaches (Germline and Somatic) and the Potential Cardiovascular Conditions They Could Treat

Figure 1

Types and Frequencies of DNA Repair in Somatic Cells After Gene Deletion by CRISPR Homolog template is almost never used, and externally provided template is used infrequently. Almost all the repair is performed using NHEJ. CRISPR = clustered regularly interspersed short palindromic repeats; DSB = double-stranded break; HDR = homology-directed repair; NHEJ = nonhomologous end-joining.

Figure 2

Types and Frequencies of DNA Repair in Germline Cells After Gene Deletion by CRISPR Unlike somatic cells, the externally provided template is not used, and NHEJ is used only one-third of the time. The homolog template (from the normal parent) is used for repair in two-thirds of cases. This form of repair is exclusive to the germline. Methods are being developed to increase homolog repair to 100% to obviate the need for pre-natal genetic diagnosis before in vitro implantation of the corrected embryo. Abbreviations as in Figure 1.