CRISPR Gene Therapy Is Here

Have you heard this science story before? Scientists used CRISPR to modify gene X in mice to do thing Y, with hopes for a treatment for disease Z. It usually takes at least ten years for a new innovation to go from theory to clinical practice. CRISPR is now over ten years old and has made its way into the hands of doctors, specifically for treating blood disorders. It's actually helping real people. It's a small number for now, but it's a good start. Let's see how researchers turned a powerful tool into medicine.

In late 2023, regulators in the UK and US approved the first gene therapy called Casgevy, using CRISPR/Cas9 technology. European regulators also gave conditional approval around the same time. Casgevy is for treating sickle cell disease and β-thalassemia, but let's focus on sickle cell today. Another treatment for sickle cell disease was also approved by the FDA at the same time, but we'll talk about that later.

More than 20 million people worldwide have sickle cell disease, which affects red blood cells. Normally, red blood cells are disc-shaped and carry oxygen with hemoglobin. However, those with sickle cell disease have a mutation in both copies of the hemoglobin gene, causing their red blood cells to become sickle-shaped.

People normally have two copies of each gene, so having one mutated hemoglobin gene and one normal gene is okay. This can even provide some protection against malaria.

But when both copies of the hemoglobin gene are mutated, that's when problems arise.

Sickle cell disease has symptoms like anemia, fever, jaundice, fatigue, and painful vaso-occlusive crises when blood flow is blocked by sticky sickle-shaped cells. It can also lead to stroke and organ damage. Treatments focus on managing symptoms, such as blood transfusions for anemia and medications to reduce blood cell clumping. Bone marrow transplants used to be the only cure, but they are painful and only available to a small number of patients. It can be challenging to find matching donors for transplants, making it difficult for many patients to receive this treatment.

Living with sickle cell disease can be challenging due to its unpredictable effects. People with the condition often have to make lifestyle adjustments to avoid triggers that can lead to a crisis. It's important for them to be aware of local medical facilities where they can seek treatment quickly. Living with sickle cell disease can be tiring and isolating, which is why a cure that doesn't require a bone marrow donor is highly desired. Casgevy is bringing a new solution to the table, using molecular biology to provide a lasting remedy for those with sickle cell disease.

In the early 2010s, Cas9 became the first approved treatment using CRISPR technology to edit human DNA and cure an inherited disorder. CRISPR was initially discovered in 1993 as a defense mechanism in archaea and bacteria against viral infections. Scientists later learned how to utilize CRISPR by creating Cas9, which acts like molecular scissors. Bacteria use Cas9 to remember the genetic code of viruses and chop them up when they attack. It's kind of like giving a hunting dog a scent to track down its prey.

Researchers have the ability to program CRISPR to target anything they choose, not just viruses. The system is incredibly specific, making DNA editing almost as accurate as editing written words. Molecular biologists are excited about this new tool because it allows them to do things they couldn't do before. Doctors can also use CRISPR for medical purposes now.

CRISPR can be used to add new information to the genetic sequence, but Casgevy just uses the scissors to disable a gene. To disable a gene, all you need to do is chop it in half. This helps with sickle cell disease by targeting the mutation in the hemoglobin gene. We all have a gene for fetal hemoglobin, which does the same job as adult hemoglobin in carrying oxygen around the body. In newborns, fetal hemoglobin sticks around for a few months before the adult hemoglobin gene is turned on.

You may have heard of baby teeth, but did you know you also have baby blood? Unlike baby teeth, your fetal hemoglobin gene is still in your DNA, but another gene is currently keeping it silent. With Casgevy using CRISPR to silence the silencer, sickle cell patients can start producing fetal hemoglobin again. There have been so many gene-editing treatments for sickle cell approved in December 2023, it's like a nickel for every one!

The second new treatment, Lyfgenia, uses an older gene editing technology called a lentiviral vector. Lentiviral vectors are not the latest trend in biotechnology, but they are considered reliable and well-studied for modifying DNA in labs and even in humans. These vectors are like a hollowed-out version of a virus, specifically a lentivirus, with only the tools needed to insert genes into cells. It's like a molecular syringe delivering a genetic shot to your cells.

n Lyfgenia, the vector delivers a gene for healthier adult hemoglobin to the patient's blood stem cells. This results in better-functioning red blood cells. However, lentivirus vector editing is not as precise as CRISPR. When the vector delivers its genetic cargo, it integrates into the cell's DNA somewhere randomly. Unlike CRISPR, researchers do not have control over where it integrates. Usually, this is not a problem.

You can reduce the chances of interruptions that may lead to serious issues like cancer. However, editing DNA always comes with some level of risk. During Lyfgenia's clinical trials, two participants developed acute myeloid leukemia, a type of blood and bone marrow cancer. Scientists carefully examined the situation to determine if Lyfgenia was the cause, but they found no connection. They checked where the modified hemoglobin had been inserted and concluded it was unlikely to cause cancer. Other factors were identified as potential contributors instead.

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 another important aspect we need to discuss - what the process of receiving both treatments actually entails. It's not as simple as getting a shot or taking a pill. First, patients must locate a medical center that is authorized to provide the treatment, which can be challenging as there are only a few dozen across the U.S. Then, there are approximately two months of regular blood transfusions to reduce the concentration of sickle cells in the bloodstream. Patients also need to take medication to boost their blood stem cells into their bloodstream, followed by a procedure where stem cells are filtered and collected for gene editing. These edited stem cells are then sent to a lab for editing using specific protocols, which can take up to six months.

Fortunately, the patient doesn't need to stay in the hospital while the stem cells are being prepared in a petri dish. Once the stem cells are ready, the patient simply returns to the treatment center to receive them. Before that, a round of chemotherapy is necessary to clear out the old, faulty stem cells. This step is important to make space for the new, edited stem cells to take their place. After the chemotherapy, the patient receives the edited cells back through infusion, and that's when we hope for the best outcome.

After spending a few more weeks in the treatment center, the patient can go home to recover from the intense process and ensure the edited cells are effective. If everything goes well, they can enjoy a life without sickle cell disease symptoms. They definitely deserve a medal for enduring all of that! Clinical trials have shown that most patients experienced a life-changing improvement. For example, 29 out of 31 patients treated with Casgevy went from having two or more vaso-occlusive crises per year to none. Similarly, 28 out of 32 patients treated with Lyfgenia had the same positive results. The results speak for themselves - it truly is life-changing.

Victoria Gray, the first Casgevy patient, recently shared her story with National Public Radio. Before Casgevy, she had to make frequent trips to the hospital for sickle cell crisis management. However, since receiving the treatment, she hasn't needed to visit a hospital in over two years. She can now keep up with her kids, work, and travel, which were all challenging tasks for her before. Both Casgevy and the other treatment mentioned work by editing blood stem cells outside the body, without changing the rest of the patient's DNA or releasing gene editing tools inside the body.

The gene editing treatment for sickle cell disease does not affect eggs or sperm, so the edited genes won't be passed on to the patient's children. There are no ethical concerns here, like in the movies. However, there are some drawbacks to consider. Both treatments require chemotherapy, which comes with its own set of side effects. While the treatment is amazing, not everyone can easily access it. Patients need to have access to a treatment center, be willing to undergo intense treatment, and be able to afford it. The cost for these treatments is high, with Casgevy priced at 2.2 million US dollars and Lyfgenia at 3.1 million. This cost, along with other barriers, may limit access to treatment in areas where sickle cell disease is most common. It's important to ensure that everyone who needs this treatment can afford and access it.

There's a positive side to this story. CRISPR has been an exciting new tool for scientists for more than a decade, and we love discovering new things. Learning helps us grow as humans, after all. But when it comes to doctors using CRISPR as a tool, that's a whole new level of excitement. We're just scratching the surface of what CRISPR can do for patient care. The possibilities are endless, and I'm sure we'll be hearing a lot more about it in the future.