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Towards PCSK9 Gene Therapy to Reduce Cardiovascular Disease Risk

The popular science article I'll point out today is indicative of the movement towards enhancement gene therapies that is taking place across the research community. More slowly in some parts than in others, but there is movement nonetheless. The enabling technologies for mammalian gene therapy have fallen greatly in cost and increased greatly in reliability over the past decade, culminating with the comparatively recent advent of CRISPR gene editing approaches. It is is thus perfectly feasible to discuss development of human gene therapies at this time, as the only remaining aspect to be brought up to the desired level of quality is the degree of cell and tissue coverage achieved by the therapy - how many cells are altered, and whether or not stem cells are altered in order to make the change more permanent. At the moment this coverage is quite variable and uncertain, so better methodologies are needed. Nonetheless, human gene therapy is possible, a few people have undergone enhancement treatments, and at the present time I'd say it is the heavy hand of regulation and a related timidity among researchers and clinicians that are the chief obstacles to be overcome.

Elective gene therapy for enhancements to the present human genome is a potentially enormous market. Unlike medicine for sick people, who comprise a small percentage of the population, this is medicine for every adult - a far greater number of individuals. So I don't believe that current regulatory stances will hold up in the face of medical tourism, not when the actual technologies are now so easily implemented by small groups. At present there are perhaps half a dozen genes for which there is enough evidence enough to feel comfortable of the safety profile of gene therapies: either existing human mutants, or animal lineages, or a great deal of research to support the alteration in question, achieved through ways other than gene therapy, such as antibody blockade of the protein produced from the genetic blueprint. That number will grow in the years ahead. The best candidates are follistatin overexpression and myostatin knockout for muscle growth and associated improvements in metabolism; there is an enormous amount of evidence in mammals for the benefits here.

Beyond this, interventions for some of the other promising genes have been observed in human and mouse mutants to significantly reduce the level of cholesterol in the bloodstream, and thus also significantly reduce cardiovascular disease incidence, with no negative side-effects. One of these is PCSK9, under discussion below, and another is ASGR1. Lowered cholesterol level is one way to reduce the impact of oxidatively damaged cholesterol on the walls of blood vessels, and thus slow the progression of atherosclerosis. This condition is essentially a positive feedback loop of tissue disruption and growth of fatty deposits in blood vessel walls, involving cholesterol, inflammation, inappropriate cell signaling, and malfunctioning immune cells. The more that any of these line items are present, the worse the situation. Interventions in any of these loop components can help to damp down the risk and pathology of atherosclerosis.

Injection could permanently lower cholesterol by changing DNA

People born with natural mutations that disable a specific gene have a lower risk of heart disease, with no apparent side effects. Now a single injection has successfully disabled this same gene in animal tests for the first time. This potential treatment would involve permanently altering the DNA inside some of the cells of a person's body, so doctors will have to be sure it is safe before trying it in people. But the benefits could be enormous. In theory, it could help millions live longer and healthier lives. The results of the animal study were described by Lorenz Mayr, of pharmaceutical firm AstraZeneca, at a genomics meeting in London. Mayr, who leads the company's research into a DNA editing technique called CRISPR, wouldn't say whether AstraZeneca plans to pursue this approach, but he was clearly excited as he presented the findings. "The idea would be to do it as a one-off. It should be permanent."

The PCSK9 protein normally circulates in the blood, where it degrades a protein found on the surface of blood vessels. This second protein removes LDL cholesterol from the blood: the faster it is degraded by PCSK9, the higher a person's cholesterol levels. But people who lack PCSK9 due to genetic mutations have more of this LDL-removal protein, and therefore less cholesterol in their blood. "They have a lower incidence of cardiovascular disease and no apparent side effects whatsoever." To mimic this effect, two companies have developed approved antibodies that remove the PCSK9 protein from the blood. These are very effective at lowering cholesterol and no serious side effects have been reported so far. It is yet to be shown if they reduce the risk of cardiovascular disease, but the first trial results are due to be announced in March.

However, the antibody drugs are extremely expensive and need to be injected every two to four weeks, so even if the antibodies work as well as hoped, they cannot be dished out to millions like statins. All attempts to develop conventional drugs to block PCSK9 have failed, but gene editing provides a radical alternative. Using the CRISPR technique, the team at AstraZeneca have disabled human versions of the PCSK9 gene in mice. They did this by injecting the CRISPR Cas 9 protein and a guiding RNA sequence into the animals. The RNA guide helps the Cas9 protein bind to a specific site in the gene. It then cuts the gene at that point, and when the break is repaired, errors that disable the gene are likely to be introduced. The big worry about using gene editing to alter DNA inside the body is that it could also cause unintended "off-target" mutations. In the worst case, these could turn cells cancerous. Mayr says the team has tested for off-target effects in 26 different tissues in the mice, and that the results will be published soon. "It's very promising in terms of safety."

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