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Applications of CRISPR-Cas9 Technology in Heart Failure and Transplantation

Diana Kim
Howard J. Eisen, MD

Drexel University College of Medicine
Philadelphia, PA, USA

As predicted, CRISPR-Cas9 has taken the field of heart failure and transplantation by storm, and we feel invigorated by recent efforts that will make tremendous impacts in patient care and research [1]. CRISPR-Cas9 is a bacterial-derived technology that takes advantage of a Cas9-induced double-strand DNA break that is then rejoined or replaced through non-homologous end joining, leading to efficient, site-specific DNA editing. As we previously discussed, CRISPR-Cas9 has tremendous implications for the field of heart failure and transplantation. Physicians and scientists must be aligned in their objectives to meet their mutual clinical needs. To this end, some major advances have recently been made.

In Nature, Ma et al. recently reported editing of the MYBPC3 mutation in human preimplantation embryos using CRISPR-Cas9 mediated targeting and repair [2]. This mutation is a dominant mutation that when expressed, causes hypertrophic cardiomyopathy, a leading cause of heart failure and the most common cause of sudden death in young, otherwise healthy adults. A single parent carrying such a dominant mutation has a 50% chance of passing this mutant gene to offspring, and inheritance of such a mutation is not often realized as the heart failure phenotype may not be evident until adulthood. CRISPR-Cas9 modification of human embryos preimplantation led to homozygous, mutation-free embryos without off-target mutations. By treating M-phase oocytes, they were able to prevent development of subsequent mosaic patterns, which could complicate preimplantation genetic diagnosis (Figure 1). This treatment has major implications for the field of heart failure for its ability to completely eradicate genetic causes of heart failure and can be a huge complement to preimplantation genetic diagnosis. As there are genetic causes of dilated cardiomyopathies, these approaches can be extended to patients with these diseases.

Figure 1

In Science, Niu et al. uses CRISPR-Cas9 to inactivate porcine endogenous retroviruses in pigs (PERVs) [3]. During xenotransplantation, the use of porcine organs is complicated by the need to achieve immunologic compatibility and the presence of retroviruses that can infect humans, potentially causing tumorigenesis and immunocompromise. Here, the authors were able to remove PERVs from primary pig fibroblasts. These reprogrammed fibroblasts are then able to produce embryos using somatic cell nuclear transfer, leading to PERV-inactivated, transgenic piglets, of which 15 are still alive and 4-months old as of the report. These pigs represent a source of tissue that may significantly improve xenotransplantation of all organs, including the heart. In particular, this technology bodes well for editing of other immunogenic genes as well as generating hearts that may be less susceptible to immunogenicity.

In the Journal of Immunology, Reyes et al. used CRISPR-Cas9 to generate pigs free of Class I MHC molecules, also known as swine leukocyte antigens (SLA), which play a major role in xenotransplant rejection. These novel pigs may reduce immunity to pig antigens during xenotransplantation, further facilitating the use of pigs as a source of organs such as the heart [4]. Additional studies have also demonstrated the ability to alter murine cardiac genes to both improve [5] and induce [6] cardiac failure.

It is clear that CRISPR-Cas9 will continue to advance its way into heart failure and transplant. In light of these major developments, it is more important than ever for physicians to be wary of the future of gene editing enabled through CRISPR-Cas9, and to continue to investigate its potential for use in current practices, not only in heart failure and transplantation but in all of medicine. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


  1. Kim, D. & Eisen, H. CRISPR-Cas9 in Heart Failure and Transplantation, by Diana Kim & Howard Eisen. ISHLT Links 8, (2016).
  2. Ma, H. et al. Correction of a pathogenic gene mutation in human embryos. Nature 548, 413-419 (2017).
  3. Niu, D. et al. Inactivation of porcine endogenous retrovirus in pigs using. Science (80-. ). 4187, 1-8 (2017).
  4. Reyes, L. M. et al. Creating Class I MHC-Null Pigs Using Guide RNA and the Cas9 Endonuclease. J. Immunol. 193, 5751-5757 (2014).
  5. Kaneko, M., Hashikami, K., Yamamoto, S., Matsumoto, H. & Nishimoto, T. Phospholamban Ablation Using CRISPR/Cas9 System Improves Mortality in a Murine Heart Failure Model. PLoS One 11, e0168486 (2016).
  6. Carroll, K. J. et al. A mouse model for adult cardiac-specific gene deletion with CRISPR/Cas9. Proc. Natl. Acad. Sci. 113, 338-343 (2016).

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