Holy crap - CRISPR is here
There’s big new stuff happening in the world of gene editing: a permanent cure for sickle cell disease through gene editing has just received FDA approval.
A lot of things get thrown about as “BIG NEWS” or “GAME-CHANGING” but it’s not an exaggeration to say that about the FDA approval of sickle cell gene editing via CRISPR.
If you’ve been reading this newsletter for a while, you may remember that I wrote about CRISPR back when Jennifer Doudna and Emmanuelle Charpentier won the Nobel Prize in the fall of 2020:
Rather than rehash the history of CRISPR or what all the articles that you can read about in the news are saying about this development, I thought I’d discuss the way a clinician thinks about the applicability of CRISPR technology more broadly in medicine.
Sickle cell is a bad disease and people who are born with it often suffer greatly
Sickle cell disease exists in the modern world because carrying sickle cell trait (inheriting one sickle cell gene) is protective against developing malaria.
The problem is that inheriting two of these genes creates the disease known as sickle cell disease, which is a lifelong problem that often leads to significant interaction with the healthcare system.
People with sickle cell disease can have a number of different chronic medical issues: infections, anemia, and vaso-occlusive events that can cause pain and damage to almost every organ system.
The treatments that we have aren’t wonderful, even though they do improve outcomes.
But even perfectly treated patients with sickle cell disease have a lifetime of medical issues - many of them deal with chronic pain, frequent hospitalizations, and a much shorter lifespan than those without sickle cell disease.
Sickle cell is the perfect disease for genetic engineering
The reason that sickle cell is the first disease to be treated with CRISPR is because it’s the perfect use case:
A really morbid disease with a high risk of major complications
A current treatment regimen that is suboptimal, even when following the standard of care
A single gene is mutated and the genetics are well understood
With sickle cell, the problem is that people don’t make the right form of hemoglobin, which is a protein in red blood cells that carries oxygen.
If you can get their bodies to produce the right protein, then you cure the disease.
And what’s what these treatments seem to do.
CRISPR is a high risk technology
My read of a lot of the media coverage is on cost and equity related to CRISPR therapy - it’s insanely expensive and there’s concern that it isn’t going to be available to everyone who might benefit.
Those are all valid concerns, but I’m not going to address them here.
It’s vital to point out that this is nascent technology - we don’t know anything about the long term outcomes and we have only a limited understanding of the complications related to treatment.
I have huge concerns about the risks of CRISPR:
Off target edits - editing a gene apart from the one that you desire to target
Unexpected editing - there are papers reporting unplanned genetic insertions that have potentially serious risks
Reducing cell fitness because of the DNA breaks used in the technology
And off-target effects have certainly been flagged in safety analyses, I’m by no means making novel points here.
But that’s why sickle cell is the perfect disease to target with this technology. We don’t have a great way to treat these patients now, and their lifelong risk of bad things happening is incredibly high.
The contrast of sickle cell with heart disease when it comes to CRISPR
I wrote about the early human trials of CRISPR technology to treat heart disease a few weeks ago, and I’m certainly not bullish on this as a use-case:
The risks of a brand new treatment are always going to be both poorly understood and difficulty to quantify.
That’s why a framework of who would most benefit from treatment is helpful, and I think the criteria I laid out above on why sickle cell is such ripe for this tech helps to encapsulate why it’s going to be a really long time before anyone considers gene editing for more common diseases that have established treatments.
If I’m considering whether a disease makes sense to have the tail risk of gene editing, I’m going to look at these 3 criteria:
Is the disease really bad? If so, it’s possible that even a pretty risky treatment has a favorable risk/benefit calculation
Are current treatments any good? If they are, I’m not sure why I’d want to expose myself or my patients to an unknown and potentially catastrophic risk when the marginal benefit on top of current treatment doesn’t seem wonderful
Is there a single genetic fix that solves the problem? If we don’t understand the genetics incredibly well, it’s no clear how much of a benefit a genetic technology will have. CRISPR isn’t going to provide a mass cure for diabetes or hypertension
You’ll notice I didn’t mention anything about cost or access, because those might be even harder problems to solve.
I’m not surprised this stuff is going to cost millions of dollars up front - but for sickle cell, I think it’s plausible that if CRISPR really does cure the disease, then it may end up being a cost-effective treatment.
For now, however, gene editing has too many unknown risks and too little that we understand about the long term benefit for it to make much sense for much of what we do in medicine.
The day may come when CRISPR is the biggest deal in medicine, but for most of us, I think that it’s less of an impactful story than Ozempic.