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.



Three big Pharma companies are developing monoclonal antibodies to the Pcsk9 protein... but if this works it would probably just be a one off lifetime treatment. So would a company that develops this have to sell it for the discounted future cash flows that would have arisen if the treatment was an antibody?

Also what are the remaining barriers to getting this treatment into clinical trials? I thought CRISPR still had a percentage or off target edits?

Posted by: Jim at June 11th, 2014 10:22 AM

I think I found a partial answer to my question - what are the remaining barriers to getting this treatment into clinical trials?

"The next step is to see how effective the therapy is in human cells, by using mice whose liver cells are replaced with human-derived liver cells, he said. Assessing safety will be the primary concern."

From a Bloomberg article and phone interview with Kiran Musunuru.

I wonder if they will be able to proceeded to human trials after that? I also saw in related news that the FDA will approve LDL lowering monoclonal antibodies that target the protein produced by the PSCK9 gene without requiring proof that they lower rates of heart disease, Sanofi and co will only have to prove that they lower LDL levels and aren't toxic. Is the FDA becoming more reasonable?

Posted by: Jim at June 12th, 2014 1:55 AM

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