First-in-human clinical trial suggests new possibility for heart disease prevention through gene editing of PCSK9 gene. Single-dose treatment maintained low cholesterol levels for at least 18 months, but further studies are needed to prove its long-term effectiveness
A week ago, an impressive medical breakthrough was announced – the kind that could change all of our lives for the better and add a few more years to our lives – and almost no one paid attention to it. The idea that was (initially) proven: a vaccine for heart disease, with just one shot.
But let's start with the basics.
Twenty years ago, medical researchers discovered that there are certain lucky people with exceptionally low levels of bad cholesterol (LDL). The low level is maintained throughout life, providing them with significant protection against heart disease. How significant? Their chance of developing heart disease is 88 percent lower than the average person. That's how low it is.
This is all great, and very happy for those people, but what about everyone else? Don't we deserve it too? Well, another study showed that this protection stems from a mutation in a gene with a particularly cruel name: proprotein convertase subtilisin-kexin type 9. For the sake of brevity, we will refer to it from now on by the common abbreviation – PCSK9. When this gene undergoes a mutation that impairs its activity, cholesterol levels in the body decrease, and the chance of heart disease drops dramatically.
Following the discovery, drugs were developed that targeted this gene. More specifically, the gene instructs cells to produce a specific enzyme, and the drugs target that enzyme. One of those drugs, for example, is called Evolocumab, really does manage to lower the levels of bad cholesterol in the body by about sixty percent. Unfortunately, people simply don't stick with taking the drug. Between a third and a half of people who take PCSK9 inhibitors decide to stop at some point. Maybe because of the side effects, maybe because of distraction, or any other reason.
But what if we could re-engineer the patients' bodies, and damage the PCSK9 gene itself? In essence, copy the same mutation that the lucky ones have, and spread it to others, in a way that would stay with them for life? What if we could give everyone one treatment that would protect them forever?
And that's exactly what the researchers did. In the new study just publishedGenetic engineering of humans to vaccinate them against heart disease.
The researchers took 35 people and gave them an unusual treatment: a solution that was injected intravenously over a four-hour period. The solution contained tiny nanoparticles that targeted liver cells, and inserted tiny biological machines into them that changed just one letter in the DNA of the PCSK9 gene. That one letter was enough to prevent the translation of this gene into an active enzyme.
That's how the treatment was supposed to work, at least, but did it work?
The results speak for themselves.
Here the results speak for themselves. All participants in the study experienced a significant reduction in their bad cholesterol levels. Those who received the highest doses of the treatment – meaning that more of their liver cells were exposed to the genetic engineering – achieved a reduction of more than eighty percent in their bad cholesterol levels. Those who received the lowest doses saw a reduction of about fifty percent in their bad cholesterol levels.
Bad cholesterol levels remained low over a year and a half of follow-up, and there's a good chance they'll stay that way for the patients' entire lives. Even if these levels remain low for just twenty years, they should reduce the risk of heart disease caused by atherosclerosis (i.e., blockage of the arteries that carry blood to the heart) by fifty percent.
But will they really do it?
This is where we need to be a little more critical. First of all, this treatment hasn't been tested on people off the street. It was developed specifically for people who suffer from a hereditary condition called hypercholesterolemia, in which the levels of bad cholesterol in their bodies skyrocket. Will it have a similar beneficial effect on regular people? Probably. Maybe. But we won't know until we try.
The other question that needs to be asked is about the side effects. The treatment that was just demonstrated had zero side effects. Only one person suffered a serious event (pneumonia) following the treatment, and the field supervisor examined him and decided that that event was not caused by the treatment. Still, it is important to check over time whether the nanoparticles did not also reach cells other than liver cells and negatively affect them. It is also necessary to make sure that the treatment did not damage unexpected areas of DNA, the kind of phenomena that cause cancer later in life. Last but not least – the experiment needs to be repeated with a larger number of participants.
Despite these caveats, it's hard not to be excited about the potential of this study. It essentially offers a type of vaccine for heart disease. Not one that completely prevents heart disease – and that's okay, because even regular vaccines don't provide complete protection – but certainly one that could reduce the incidence of atherosclerosis by tens of percent… in a single shot.
And he won't be the only one.
Imagine a world where similar preventive treatments exist for cancer. For neurodegenerative diseases like Alzheimer's or Parkinson's. For diabetes and osteoporosis and any other disease you can think of. It sounds like a fantasy, but there is no physical or biological principle that should prevent us from realizing these treatments with sufficiently advanced scientific and technological tools. And this particular treatment provides reason for optimism that we are on the way to that world.
for life.
Quick FAQ
Is this a regular vaccine?
No. This is a one-time gene therapy that changes the activity of the PCSK9 gene and does not work like a vaccine against viruses or bacteria.
How much did cholesterol levels drop?
Some participants experienced a more than 80% reduction in LDL levels.
Who is the treatment intended for today?
The trial was conducted in patients with familial hypercholesterolemia, not in the general population.
Is the treatment already approved for use?
No. This is still early clinical research and larger trials are needed.
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