Stop me if you’ve heard a science story like this before: Scientists used CRISPR, a powerful gene editing tool, to modify gene X in mice to do thing Y, which they hope could one day lead to a treatment for disease Z. Maybe you even heard it from us. And maybe you thought, that’s cool if it ever happens, and then you just didn’t think about it anymore.
Well, here’s the thing. It’s often said that it takes at least ten years for a new innovation to make its way from theory into clinical practice. And CRISPR, as a gene editing tool, passed that birthday not too long ago.
That’s right: CRISPR-based gene editing has made its way into the hands of doctors, specifically as a treatment for blood disorders. It’s making real differences in the lives of real humans. A pretty small number of them, but hey, it’s a start.
Let’s take a closer look at how researchers turned a powerful, but abstract, tool into medicine. [♪ INTRO] At the end of 2023, medical regulators in the United Kingdom and the United States approved the world’s first CRISPR/Cas9-based gene therapy, called Casgevy. European regulators also granted a conditional approval shortly before we filmed this.
Casgevy is designed to treat two blood disorders: sickle cell disease and β-thalassemia. We’re focusing on sickle cell today. The U.
S. Food and Drg Administration approved a second similar treatment for sickle cell disease at the same time, but we’ll come back to that one. There are more than 20 million people worldwide who are living with sickle cell disease.
It’s a condition that affects red blood cells, which are normally disc-shaped and full of hemoglobin, a molecule that carries oxygen. But people with sickle cell disease have a mutation in both copies of the gene for hemoglobin that causes their red blood cells to turn into a kind of sickle shape. Everyone has two copies of almost every gene, so it’s possible to have one copy of the sickle cell mutation and one typical hemoglobin gene, and be basically fine.
Also slightly safer from malaria but that’s a whole other story. But when both copies of the hemoglobin gene have the sickle cell mutation, that’s when there’s trouble. Symptoms of sickle cell disease include anemia, fever, jaundice, fatigue, and vaso-occlusive crises, which are unpredictable episodes of extreme pain that happen when the sickle-shaped cells stick together and block blood flow.
Sickle cell disease can also cause stroke, even in children, and other organ damage that gets worse over time. Treatments have mostly focused on management. Blood transfusions treat anemia by providing healthy blood cells, and medications that reduce the clumpiness or sickle-shaped-ness of sickle cells make vaso-occlusive crises less common.
But the first, and for a long time the only, cure for sickle cell was a bone marrow transplant, a painful procedure that is only available to young patients with severe symptoms. Less than 20% of patients who would be eligible for a bone marrow transplant can find a matching donor. So it’s far more common that people with sickle cell disease have to find ways to live with its unpredictable effects.
They might avoid situations that can trigger a crisis, like sudden temperature changes, and take note of local sickle cell day hospitals and emergency rooms where they can get treatment for an episode on short notice. As you can imagine, living with sickle cell disease is exhausting and isolating, and a cure that doesn’t require a bone marrow donor is incredibly desirable. Enter Casgevy, kicking in the door and turning the new hotness in molecular biology into a real, lasting solution to all of that.
By new, I mean around the early 2010s, keeping in mind that ten year rule of thumb. Casgevy is the first approved treatment using CRISPR-Cas9 to edit human DNA and cure an inherited disorder. CRISPR was first described in 1993, when researchers found it lurking in archaea and bacteria, providing defense against viral infections.
It wasn’t until more recently that scientists worked out how to turn it to their advantage. CRISPR creates Cas9, which is like a pair of molecular scissors with a customizable targeting system. Bacteria use it to defend against viral infections by remembering the genetic code of an attacker.
They load that code to Cas9 like giving a hunting dog a scent, and then it can match up with a viral attacker and chop its genetic information to bits. Researchers can program CRISPR’s targeting system to go after anything they like, not just an invading virus. And that system is so specific that it makes editing DNA almost as precise as editing the words I’m reading on this teleprompter.
You can see why molecular biologists love this thing so much – that was something they couldn’t do before. And now, doctors can use it too. There are ways to use CRISPR to add new information into the genetic sequence, but Casgevy just uses the scissors.
Because while it’s not quite as simple as it sounds, all you really need to do to disable a gene is… chop it in half. That helps us with sickle cell disease in a roundabout way. So, we know that the problem in sickle cell is a mutation in the hemoglobin gene.
But it turns out, we all have another gene for another hemoglobin. Fetal hemoglobin does the same job as adult hemoglobin. It carries oxygen around the body, but in the fetus.
It sticks around in newborns for a few months, until that gene gets turned off and the adult hemoglobin gene gets turned on. You’ve heard of baby teeth? Bet you didn’t know you had baby blood.
And, unlike baby teeth, you don’t trade your fetal hemoglobin gene for a quarter under your pillow. It’s still in your DNA, but another gene is silencing it. Casgevy uses CRISPR to silence the silencer so that the sickle cell patient’s red blood cells start making fetal hemoglobin again.
But if I had a nickel for every gene-editing treatment for sickle cell approved in December of 2023… well, you know how this one goes. The second new treatment, Lyfgenia, makes use of an older gene editing technology called a lentiviral vector. While they’re not the cool new kid on the biotechnology block, lentiviral vectors are generally seen as a reliable, well-studied tool for modifying DNA in a lab setting, and even in humans.
They don’t have any of the sick-making guts of a standard virus. Instead, a type of virus called a lentivirus has been hollowed out to basically just be an envelope. It still has the tools the virus would normally use to break into your DNA, but with everything else gone, there’s space for scientists to package whatever gene they want.
So the virus is almost like a molecular syringe, delivering a genetic shot right into your cells. In the case of Lyfgenia, the vector delivers a gene for an anti-sickling version of adult hemoglobin to the patient’s blood stem cells. That results in healthier, more typically functioning red blood cells.
But lentivirus vector editing lacks the precision of CRISPR. When the vector drops off its genetic cargo, it gets integrated into that cell’s DNA… somewhere. In contrast to CRISPR, researchers don’t get to pick where.
Most of the time, that’s fine. There are ways to reduce the chances that it interrupts something important, which could lead to something like cancer. But when you’re editing DNA, there is always some risk.
During the first round of Lyfgenia’s clinical trials, two participants developed acute myeloid leukemia, which is blood and bone marrow cancer. The scientists closely analyzed the situation to see if and how Lyfgenia was related. They concluded that there was no connection.
They checked where their modified hemoglobin had been inserted, and it wasn’t anywhere likely to break something and lead to cancer. Instead, they point to a few other factors. People with sickle cell disease already have about twice the risk of leukemia compared to people without sickle cell.
And the chemotherapy that’s used as part of the treatment can also cause cancer. Lastly, these cases of leukemia occurred in the first round of human clinical trials for Lyfgenia, and the researchers later concluded that not enough of the modified cells were transplanted to the patients. Not having enough blood stem cells could stress out the body and increase the risk of cancer developing.
For the second and third round of clinical trials, the company that makes Lyfgenia says that they refined their manufacturing process to reduce the risk of cancer as a side effect. Lyfgenia’s approval from the FDA came with a “black box warning,” which means that anyone who gets this treatment should expect lifelong monitoring for blood cancer afterward. There is one other serious issue we haven’t talked about yet.
And that’s what getting both of these treatments actually looks like. It’s not… quite as easy as getting a shot or swallowing a pill. First, patients need to find a medical center that’s authorized to provide the treatment.
There are only a few dozen of these across the U. S. , never mind worldwide, and most people don’t live near one.
Then, there are about two months of regular blood transfusions to reduce the concentration of their own sickle cells in their bloodstream. Then, the patient takes medication to boot their blood stem cells from their bone marrow into their bloodstream. A machine filters those stem cells out and collects them to have their genes edited.
Those stem cells go to a lab to be edited using either Casgevy or Lyfgenia’s protocols. This step takes up to six months. Luckily, because the stem cells are in a petri dish somewhere and not the patient, the patient doesn’t have to stay in the hospital while this is happening.
When the stem cells are ready, the patient returns to the treatment center to get ready for their new cells. And all this part really involves is a casual, relaxing, easy round of chemotherapy to murder all their bone marrow. There’s not really a way around this, because doctors have to get rid of all the old, faulty stem cells that make sickle cells, to make room for the edited stem cells to move in.
Which is hopefully what happens next, when the patient gets their edited cells back by infusion. After a few more weeks in the treatment center to recover from this intense process, and to make sure that the edited cells take effect, the patient can go home. And then, if everything works the way it should, they can live a life free from sickle cell disease symptoms.
And also, they should get a medal for going through all that. In clinical trials, most patients saw a life-changing improvement. For 29 of 31 patients treated with Casgevy, they went from two or more vaso-occlusive crises per year, to none.
And the same was true for 28 of 32 patients treated with Lyfgenia. But you don’t have to take my word for the life-changing-ness. The first Casgevy patient, Victoria Gray, shared her story with National Public Radio.
Before Casgevy, she averaged seven trips to a hospital or emergency room every year to manage a sickle cell crisis. Since getting the treatment, she hasn’t been to a hospital in over two years, and she has been able to keep up with her four kids, hold down a job, and travel – things that were really difficult to do before. There are a few more things both of these treatments have in common that I ought to mention.
Both work by editing blood stem cells outside of the body, so the rest of the patient’s DNA is unchanged, and there are no gene editing tools set loose inside of their body. That also means that the gene editing does not affect eggs or sperm, so the sickle cell-curing edits can’t be passed on to the patient’s children. There’s no Hollywood “scientists didn’t stop to think about whether they should” nightmares here.
That doesn’t mean there aren’t some relevant drawbacks. Both treatments require chemotherapy, and that means all the side effects that go with it. Clearly, that’s worth it to these patients, but it can’t be something they undertook lightly.
And while this technology is awesome, getting the treatment to all of the people who need it is another story. There’s the stuff we already talked about – having access to a treatment center, and having the willingness and means to go through grueling rounds of treatment. But most importantly, you or your insurance company are going to have to foot the bill.
The going price for Casgevy is 2. 2 million US dollars, and for Lyfgenia, it’s 3. 1 million.
That price tag, along with the other barriers, is likely to limit access to treatment precisely in the places where sickle cell is most common. Curing a devastating disease only in the privileged… it ain’t a great look. There is a bright side, though.
For over a decade, CRISPR was a fun new toy for scientists. And we like those. We like learning new things, because knowing stuff is just great for humans, in general.
A fun new toy for doctors? That’s something else again. This is only the very beginning of the use of CRISPR in patient care.
The floodgates are open, and I have no doubt we haven’t heard the last of it. Thanks for watching this episode of SciShow, and thanks to the patrons on Patreon who made it possible. We couldn’t do this without your support, so thank you.
