Engineering a Loss of Function PCSK9 Mutation to Reduce Cardiovascular Disease Risk

The advent of efficient techniques for gene editing such as CRISPR is moving us into an era in which all sorts of beneficial enhancements to human biology become possible. The regulatory establishment is exceedingly conservative with regard to genetic alterations and will vigorously resist all such treatments, of course, but gene therapies with good evidence of beneficial effects will become available via medical tourism in the same way as stem cell treatments did more than a decade ago. Myostatin knockout is a good example of a possible target of benefit to basically healthy people as well as those suffering age-related frailty, as it induces greater muscle mass and growth. But there are many other possible targets for gene therapies, such as the example here:

Individuals with naturally occurring loss-of-function PCSK9 mutations experience reduced blood low-density lipoprotein cholesterol (LDL-C) levels and protection against cardiovascular disease. The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system can efficiently introduce loss-of-function mutations into the endogenous PCSK9 gene in vivo.

We used adenovirus to express Cas9 and a CRISPR guide RNA targeting Pcsk9 in mouse liver, where the gene is specifically expressed. We found that within three to four days of administration of the virus, the mutagenesis rate of Pcsk9 in the liver was as high as 50% or more. This resulted in decreased plasma PCSK9 levels, increased hepatic LDL receptor levels, and decreased plasma cholesterol levels (by 35%-40%) in the blood. No off-target mutagenesis was detected in 10 selected sites.

Genome editing with the CRISPR-Cas9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice. This approach may have therapeutic potential for the prevention of cardiovascular disease in humans.