The First CRISPR Gene Therapy Is Here

Stop me if you've heard a science story like this before: Scientists used CRISPR, a powerful

gene

-editing tool, to modify

gene

Z. Maybe you even heard it from us. And maybe you thought, that's fine if it ever happens, and then you just didn't think about it anymore. Well,

here

's the thing. It is often said that it takes at least ten years for a new innovation to move from theory to clinical practice. And CRISPR, as a gene editing tool, turned that year not long ago. That's right: CRISPR-based gene editing has found 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 fairly small number of them, but hey, it's a start. Let's take a closer look at how researchers turned medicine into a powerful but abstract tool. In late 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 conditional approval shortly before we filmed this. Casgevy is designed to treat two blood disorders: sickle cell anemia and β-thalassemia. Today we will focus on sickle cells. The U.S. Food and Drug Administration approved a second, similar treatment for sickle cell anemia at the same time, but we'll come back to that one.

T

here

are more than 20 million people worldwide living with sickle cell disease. It is a condition that affects red blood cells, which are normally disc-shaped and filled with hemoglobin, a molecule that carries oxygen. But people with sickle cell anemia have a mutation in both copies of the hemoglobin gene that causes their red blood cells to become somewhat sickle-shaped. Everyone has two copies of almost every gene, so it is possible to have one copy of the sickle cell mutation and a typical hemoglobin gene and be basically fine. It's also a little safer against malaria, but that's another story.

But when both copies of the hemoglobin gene have the sickle cell mutation, that's when the problem arises. Symptoms of sickle cell anemia include anemia, fever, jaundice, fatigue, and vaso-occlusive crises, which are unpredictable episodes of extreme pain that occur when sickle cells join together and block blood flow. Sickle cell anemia can also cause strokes, even in children, and other organ damage that worsens over time. Treatments have focused primarily on management. Blood transfusions treat anemia by providing healthy blood cells, and medications that reduce the clumping or sickling of sickle cells make vaso-occlusive crises less common. But the

first

, and for long the only, cure for sickle cell anemia 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 compatible donor. Therefore, it is much more common for people with sickle cell anemia to have to find ways to live with its unpredictable effects. They could avoid situations that could trigger a crisis, such as sudden changes in temperature, and take note of local day hospitals and sickle cell emergency rooms, where they can receive treatment for an episode on short notice. As you can imagine, living with sickle cell disease is exhausting and isolating, and a cure that does not require a bone marrow donor is incredibly desirable.

Enter Casgevy, kicking in the door and turning the new appeal of molecular biology into a real, lasting solution to all that. By new I mean the early 2010s, taking into account the ten-year rule of thumb. Casgevy is the first approved treatment that uses CRISPR-Cas9 to edit human DNA and cure an inherited disorder. CRISPR was first described in 1993, when researchers discovered that it lurked in archaea and bacteria, providing defense against viral infections. It wasn't until recently that scientists figured out how to take advantage of it. CRISPR creates Cas9, which is like molecular scissors with a customizable targeting system.

Bacteria use it to defend themselves against viral infections by remembering an attacker's genetic code. They load that code into Cas9 like they've given a scent to a hunting dog, and then it can match a viral attacker and cut their genetic information into pieces. Researchers can program the CRISPR targeting system to go after anything they want, not just an invading virus. And that system is so specific that it makes editing the DNA almost as precise as editing the words I'm reading on this teleprompter. You can see why molecular biologists love this 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 to the genetic sequence, but Casgevy is limited to using scissors. Because while it's not as simple as it seems, all you really need to do to turn off a gene is... cut it in half. That helps us with sickle cell anemia indirectly. So, we know that the problem in sickle cell anemia is a mutation in the hemoglobin gene. But it turns out that we all have another gene for another hemoglobin. Fetal hemoglobin does the same job as adult hemoglobin. It carries oxygen throughout the body, but in the fetus.

It remains in newborns for a few months, until that gene is deactivated and the adult hemoglobin gene is activated. Have you heard about baby teeth? I bet you didn't know you had baby blood. And unlike baby teeth, you don't trade in 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 producing fetal hemoglobin again. But if I had a nickel for every gene-editing treatment for sickle cell disease approved in December 2023... well, you know how this one goes.

The second new treatment, Lyfgenia, uses an older gene-editing technology called a lentiviral vector. While not the new kid on the biotechnology block, lentiviral vectors are generally considered a reliable and well-studied tool for modifying DNA in a laboratory, and even in humans. They don't have any of the sick guts of a standard virus. Instead, a type of virus called a lentivirus has been hollowed out to essentially turn it into an envelope. You still have the tools the virus would normally use to get into your DNA, but since everything else is gone, there's room for scientists to pack in whatever genes they want.

So the virus is almost like a molecular syringe that delivers a genetic injection directly into 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. This results in healthier, more normally functioning red blood cells. But lentivirus vector editing lacks the precision of CRISPR. When the vector abandons its genetic load, it integrates into the DNA of that cell... somewhere. Unlike CRISPR, researchers can't choose where. Most of the time, that's fine. There are ways to reduce the chances of you interrupting something important, which could lead to something like cancer.

But when editing DNA, there is always some risk. During the first round of Lyfgenia clinical trials, two participants developed acute myeloid leukemia, which is a cancer of the blood and bone marrow. Scientists took a closer look at 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 likely to break something and cause cancer. Instead, they point to some other factors. People with sickle cell anemia already have about twice the risk of developing leukemia compared to people without sickle cell anemia.

And the chemo

therapy

used as part of the treatment can also cause cancer. Finally, these leukemia cases occurred in the first round of human clinical trials of Lyfgenia, and researchers later concluded that not enough modified cells were transplanted into the patients. Not having enough blood stem cells could stress the body and increase the risk of developing cancer. For the second and third rounds of clinical trials, the company that makes Lyfgenia says they refined their manufacturing process to reduce the risk of cancer as a side effect. The FDA's approval of Lyfgenia came with a "black box warning," meaning anyone receiving this treatment should expect lifelong follow-up for blood cancer later.

There is another serious problem that we haven't talked about yet. And this is what it actually looks like to receive both treatments. It's... not as easy as getting a shot or swallowing a pill. First, patients must find a medical facility that is licensed to provide the treatment. There are only a few dozen of these in the entire United States, let alone the entire world, and most people don't live near one. Then there are about two months of regular blood transfusions to reduce the concentration of your own sickle cells in the bloodstream. The patient then takes medications to transport the blood stem cells from the bone marrow to the bloodstream.

A machine filters out those stem cells and collects them to edit their genes. Those stem cells go to a laboratory to be edited using the Casgevy or Lyfgenia protocols. This step takes up to six months. Fortunately, because the stem cells are somewhere in a petri dish and not the patient, the patient does not have to stay in the hospital while this happens. When the stem cells are ready, the patient returns to the treatment center to prepare for the new cells. And all this part really entails is a casual, relaxing, easy round of chemotherapy to kill all your bone marrow.

There's really no way around this, because doctors have to get rid of all the old, defective stem cells that produce sickle cells, to make room for the edited stem cells to move. Which is hopefully what happens next, when the patient receives their edited cells via infusion. After a few more weeks at the treatment center to recover from this intense process and ensure that the edited cells take effect, the patient can go home. And then, if everything works as it should, they will be able to live a life free of the symptoms of sickle cell anemia. And they should also get a medal for going through all that.

In clinical trials, most patients saw life-changing improvement. In 29 of 31 patients treated with Casgevy, they went from two or more vaso-occlusive crises per year to none. And the same happened with 28 of 32 patients treated with Lyfgenia. But you don't have to take my word for life changing. Casgevy's first patient, Victoria Gray, shared her story with National Public Radio. Before Casgevy, she averaged seven trips to the hospital or emergency room each year to manage a sickle cell crisis. Since she received treatment, she has not been in a hospital in over two years and has been able to keep up with her four children, hold down a job and travel, things that were really difficult to do before.

There are a few more things that both treatments have in common that I should mention. Both work by editing blood stem cells outside the body, so the rest of the patient's DNA is unchanged and there are no gene editing tools loose inside her body. That also means that the gene editing does not affect eggs or sperm, so the edits that cure sickle cells cannot be passed on to the patient's children. No Hollywood nightmares here "scientists didn't stop to think if they should have" nightmares. That doesn't mean there aren't some relevant drawbacks. Both treatments require chemotherapy, and that means all the side effects that come with it.

Clearly, that's worth it for these patients, but it can't be something they took lightly. And while this technology is amazing, getting the treatment to everyone who needs it is another story. There are the things we already talked about: having access to a treatment center and having the will and means to go through grueling rounds of treatment. But most importantly, you or your insurance company will have to foot the bill. The current price of Casgevy is $2.2 million and Lyfgenia is $3.1 million. That price, along with other barriers, is likely to limit access totreatment precisely in the places where sickle cell anemia is most common.

Curing a devastating disease only among the privileged... is not a good idea. However, there is a positive side. For more than a decade, CRISPR was a fun new toy for scientists. And we like those. We like to learn new things, because knowing things is great for humans in general. A fun new toy for doctors? That's something else again. This is just the beginning of using CRISPR in patient care. The floodgates are open and I have no doubt we haven't heard the last of it yet. Thank you for watching this episode of SciShow and thank you to the Patreon patrons who made it possible.

We couldn't do this without your support, so thank you.