Will This Gene Editing Breakthrough Eliminate Heart Disease?
A new CRISPR gene-editing therapy just lowered LDL by 62% with one injection. But the real breakthrough isn’t cholesterol…
A massive new paper just dropped in the New England Journal of Medicine days ago on gene therapy for lowering LDL cholesterol.
And it’s breaking headlines.
Now, I realize that sentence, and the associated headlines, are going to provoke two polar-opposite reactions.
On one hand, we have those pronouncing: “We are curing heart disease with one shot!”
On the other, we have those warning: “This is ridiculous. Why would you lower LDL cholesterol with gene therapy? This is pure idiocy.”
Everyone seems to have an opinion.
But everyone also seems to be missing the real story here…
Because there is a breakthrough here worth being excited about. But it’s not what you think.
So, today, I want to dig into this landmark paper and reveal to you why I had a grin stretched ear-to-ear while reading it.
The Real Science Behind the “Cure Heart Disease” Headlines
Okay, first let me quickly explain what this paper was — and what it wasn’t.
It was not a signed-and-sealed approval making gene therapy the new standard of care for LDL lowering.
It was a Phase 1 open-label trial testing a new technology called VERVE-102, developed by Verve Therapeutics (part of Eli Lilly). Specifically, it tested a CRISPR-Cas9-based gene-editing therapy designed to lower PCSK9 levels specifically in the liver.
Okay… let’s unpack that gobbledygook, because what’s happening biologically is more precise than most people realize.
The goal here was not to gene-edit an entire human being indiscriminately. Rather, this was a highly targeted therapeutic approach aimed specifically at the liver.
The VERVE-102 system contains:
A gene base editor, termed adenine base editor (ABE; red), which changes essentially one “letter” (adenine) in the gene coding for the PCSK9 protein
A guide RNA (blue), which acts like a homing device to direct the editor to the correct place in the genome.
Ironically, that’s the easy part.
The difficult part — and historically the biggest barrier in human gene-editing therapies — is getting the entire editing complex to the right tissue and organs in the body.
And this is where the story gets more interesting.
They solved that delivery problem using a lipid nanoparticle containing N-acetylgalactosamine (GalNAc; pink, above), which enables entry into liver cells by binding to a receptor called the asialoglycoprotein receptor (red circle, below).
Another way to think about it is this:
Gene editor = the letter
Lipid nanoparticle = the envelope
GalNAc = the stamp that tells the body to deliver the package to the liver.
Additionally, the researchers didn’t select random participants.
They specifically enrolled people with premature cardiovascular disease, most of whom also had familial hypercholesterolemia: a genetic condition that impairs the clearance of cholesterol-containing particles like LDL.
And to be completely clear about my opinion: I think this is exactly the right population in which to test this technology.
These are highly vulnerable individuals, many with a strong genetic predisposition to disease, where the therapy is essentially attempting to correct a biologically rooted defect, at least in the 83% with familial hypercholesterolemia.
Does that all make sense?
One Injection, 62% Lower LDL
Now, the headline result was, of course, that a single administration was highly effective at lowering LDL cholesterol.
Specifically, at the highest dose (1 mg/kg, administered to seven participants) the average percent change in LDL cholesterol was 62% (dark blue).
And this reduction was largely maintained over time.
So, you can see where people got the idea that a single injection could protect people from cardiovascular disease for life.
Obviously, that requires extrapolation, even on the durability of the treatment. For the most part, they only looked at a maximum 1-year timeframe. But you can see where the headlines and hype came from.
Additionally, I’ll be very clear about this: this study reported no improvements in cardiovascular or health outcomes.
They were looking at biomarkers.
And because this was a Phase 1 trial, it was primarily a safety trial, not a trial designed to assess cardiovascular outcomes.
Now, if you want my speculation: cardiovascular risk, yes.
Overall health? It probably depends on the population.
If we’re talking about metabolically healthy people with high LDL and ApoB, I think it would be borderline insane to administer this therapy today.
This is not the next evolution of peptides for your average biohacker bro… although if tomorrow I saw a YouTube video by Bryan Johnson entitled, “I Verved My Liver,” I wouldn’t be entirely surprised.
Sorry… a little inside baseball there. Just a light-hearted joke!
But Was It Safe?
However, what about safety? That was the main objective of the trial.
Well, on balance, there were very few meaningful adverse events reported.
Transient infusion-related reactions occurred, but they were not severe.
There was a small bump in a liver marker called ALT early in the post-dose period, but that largely resolved.
There was only one serious adverse event: a condition called aspiration pneumonitis. But this occurred in someone with a history of gastroesophageal reflux, and the adverse event was not considered related to the treatment.
So, was it safe? Based on the reported data, it appears so.
Furthermore, something I found reassuring was that the delivery system (the GalNAc lipid nanoparticle) cleared from the body very quickly. Its half-life was less than 20 hours. So, within a couple of days, the delivery system was basically gone.
In other words, if we go back to our letter-and-envelope analogy, the envelope was pretty much shredded and discarded, with very little debris left within a couple of days.
All else being equal, that’s probably a good thing.
The TL;DR is:
The injection was effective at delivering the gene-editing system where it was supposed to go — to the liver — making a modification and then clearing out.
Additionally, prior evidence suggests very little distribution of the gene-editing technology across other organs, like the adrenal glands and spleen.
And, importantly, at least in a mouse model, there was no transmission to the next generation.
So, we’re not editing the human germline here.
Taken together, my honest assessment is that:
This technology appears rather specific and generally safe in the acute sense for targeting PCSK9 in the liver and lowering LDL cholesterol in patients with genetic familial hypercholesterolemia or premature cardiovascular disease.
Why This Is Different Than a Statin
But now I should probably delve a little deeper into the downstream effects of this medication, i.e. how it lowers LDL.
And I want to parse the difference between this technology and something like a statin.
Statins inhibit an enzyme involved in cholesterol synthesis. So, your body makes less cholesterol in the liver and elsewhere. (A downstream consequence, in fairness, is that LDL receptors are also unregulated.)
Here, we’re doing something mechanistically different.
The PCSK9 protein promotes the destruction of LDL receptors, which are important for clearing particles out of the bloodstream faster.
Physiologically, I think this is a better approach, caveating that this is my opinion.
And I’ve gone on the record before saying that, if I had to choose between taking a statin and a PCSK9 inhibitor, I would take the PCSK9 inhibitor.
So, if you want an honest, non-hyped assessment of this literature (again), here it is:
This was a breakthrough proof-of-concept safety trial demonstrating that targeted delivery of gene-editing technology to the liver can successfully make a specific genetic modification.
In other words, the technology works.
And as far as we can tell from this early-stage trial, it also appears reasonably safe.
Technologically speaking, I do consider that a genuine breakthrough.
But in my opinion, the headlines actually understate what’s truly exciting here.
Because the real breakthrough is not simply: “We can lower LDL cholesterol with one injection.”
The real breakthrough is that we are beginning to demonstrate the ability to deliver highly targeted gene-editing machinery to a specific organ, make a precise modification, achieve a desired physiological effect, and then have the delivery system rapidly clear from the body.
That is a therapeutic paradigm shift.
And that’s what I want to spend the rest of this letter talking about, because this isn’t the end of the discussion. It’s the beginning…
In the rest of this letter for StayCurious Metabolism Premium members, we will delve into:
How the technology could become a springboard for far greater innovations, including Alzheimer’s prevention
Obstacles that still remain in pursuing these advancements (and ways we could get into the brain)
The unusual way I lowered my LDL and ApoB by 71% (no statin, PCSK9 inhibitor, gene therapy, or Oreos)
The ethics, and why “playing God” is often framed incorrectly
If you’re someone who appreciates nuanced science and a truly open-minded exploration of the frontier of metabolic health, rather than influencers simply pandering to dogma, then this is the community for you. And I’d love to welcome you into it.
