The Heart Attack Cure: Vaccinating Against Cardiovascular Disease

Vaccination against infectious disease has improved health and well-being on a global scale. Decades of data support vaccination as among the most efficient means of promoting individual and public health. The WHO attributes the benefits of vaccination programs as second only to clean water in eliminating many diseases that were once common.

The undeniable success of vaccination has prompted researchers to investigate potential applications outside of infectious diseases. According to the latest WHO reports, cardiovascular disease (CVD)² accounts for 32% of all deaths globally and is the most common cause of death worldwide. Most of these CVD deaths occur in developing nations where access to preventative healthcare is limited.

The benefit of preventive therapy to reduce CVD has been well documented. Current interventions include dietary modification, increased exercise, and lipid-lowering pharmaceuticals. However, CVD progresses over decades, and all current therapies require lifelong vigilance. Poor patient compliance and lack of pharmaceutical access are significant barriers to CVD prevention.

A simple 1-time intervention (like with vaccines) would be of great benefit, particularly in developing nations. An innovative potential solution was discussed in the March 2018 issue of Nature (1). The intervention targets proprotein convertase subtilisin/kexin type (PCSK9), a protein that facilitates the recycling of lipid receptors at the surface of hepatocytes. Loss-of-function PCSK9 mutations are associated with lower concentrations of LDL and a reduced incidence of CVD. Several new monoclonal antibody pharmaceuticals inhibit PCSK9 for this purpose.

In the study, researchers used the clustered regularly interspaced short palindromic repeats (CRISPR) gene-editing technique. A CRISPR construct that introduced site-specific nonsense mutations in the PCSK9³ gene was developed. The nonsense mutations were analogous to the beneficial mutations identified in humans. This construct was then packaged into an adenovirus and delivered to hepatocytes of living mice. A single injection reduced the plasma concentrations of PCSK9 by 50% and LDL cholesterol by 30%. The reduction remained stable with no apparent off-target mutations at 4 weeks.

Despite what the well-intended but uninformed antivaccine supporters would have you believe, the risk-to-benefit ratio for current vaccines is essentially zero. Gene-editing therapy targeting a rare disease or small population can tolerate some risk. However, any gene-editing therapy issued to the general population needs to be 100% safe, at least to the same degree as current infectious disease vaccines.

For a CVD prevention treatment to be effective, it would need to be given early in life before any disease progression. However, the long-term safety of in vivo gene editing by CRISPR is not known. Potential side effects include off-target binding of the CRISPR construct or inappropriate repair of the artificially introduced mutations. Both scenarios could lead to a malignant mutation.

A single-dose cure for heart disease may be one step closer. How big a step was taken remains to be seen.

• Received for publication May 25, 2018.
• Accepted for publication May 31, 2018.

• © 2018 American Association for Clinical Chemistry