[Previous: The coming age of genetic therapy]
We’re living at the dawn of a revolutionary new era of medicine. The U.K. has just approved, and the U.S. is expected to approve, the first gene-editing cure for sickle cell disease:
In a world first, U.K. regulators yesterday approved a therapy that uses the gene-editing technique CRISPR. The approach treats two inherited blood disorders, including sickle cell disease, which afflicts mostly people of African ancestry, by modifying a patient’s blood stem cells in the lab and returning them.
…In clinical trials, all but one of 29 people who have received the treatment for sickle cell started to make fetal hemoglobin and no longer had severe pain episodes; and 39 of 42 patients who received it for a related disorder, beta thalassemia, no longer needed blood transfusions to avoid severe anemia. Unlike bone marrow transplants, the one available cure for these diseases if a matching donor can be found, the infusion of a patient’s own edited cells does not pose a risk of immune system rejection.
“United Kingdom approves first-ever CRISPR treatment, a cure for sickle cell disease and beta thalassemia.” Jocelyn Kaiser, Science, 16 November 2023.
As you probably know, sickle cell disease is a genetic disorder caused by a mutation in hemoglobin, the protein that transports oxygen in blood. This mutation is most common among people of African ancestry, and it persists because it has a selective advantage. A person with one copy of the gene has extra resistance to malaria, which is one of the great scourges of humanity.
But a person with two copies has abnormal, sickle-shaped red blood cells. The misshapen cells get jammed up in small capillaries and cut off blood flow, causing agonizing pain, anemia, organ damage, and shortened lifespan.
Sickle cell disease is caused by a single-nucleotide polymorphism: an A that’s changed to a T in one of the genes that codes for a component of hemoglobin. I assumed the treatment would edit this gene to its correct form, but that’s not how it works.
Instead, scientists use CRISPR to disable a different gene, BCL11A, which controls the production of a different kind of hemoglobin that’s usually only active in fetuses and infants.
Once this regulatory gene is switched off, the body begins making fetal hemoglobin, which takes up the slack for the defective form. As a bonus, this change also treats beta-thalassemia, a related disorder where the body doesn’t make enough hemoglobin.
The costs and the drawbacks
There were already genetic therapies on the market, like one for a condition called spinal muscular atrophy, or another for hemophilia, or another for a rare form of blindness. These treatments rely on viral vectors to deliver a fixed copy of a defective gene.
However, this method has some drawbacks. Sometimes the immune system flags the virus and attacks it, causing the treatment to fail. Also, the most common viral vector for genetic therapy, adeno-associated virus or AAV, doesn’t integrate the new gene into the cell’s genome, but deposits it as a free-floating package called an episome.
This is beneficial in some ways. It avoids the risk of viral insertion disrupting an existing gene, which can cause cancer and other problems. But it also means that as cells divide and die, the new gene gets diluted away. That makes this therapy best suited for long-lived cell types that undergo little turnover, like neurons.
CRISPR therapies should avoid these problems. Doctors sample the patient’s bone marrow, filter out stem cells, and do the genetic edit. As with any other bone marrow transplant, the patient has to get chemotherapy to wipe out their original stem cells, so that the edited cells, when transfused back into the body, get a foothold and start multiplying. They may have to spend up to a month in the hospital to make sure the new cells take.
The full course of treatment could cost up to $2 million. That price tag is a heavy burden even in wealthy nations, and it’s far out of reach for developing countries. However, it could still be cost-effective if it restores decades of healthy, pain-free life.
The other drawback is that this approach isn’t yet feasible for other kinds of genetic diseases. Blood disorders like sickle-cell disease are the easiest to treat, because it’s straightforward to harvest cells from blood or bone marrow, edit them in a lab and re-transfuse them. This won’t work for other organs. The holy grail is in vivo treatment—targeted editing of DNA inside the body.
How far and fast
Still, we shouldn’t overlook how far we’ve come, and how fast. The Nobel Prize-winning paper by Jennifer Doudna and Emmanuelle Charpentier that demonstrated the utility of CRISPR as a gene-editing tool was only published in 2012. From laboratory proof-of-concept to approved treatment for humans took just eleven years, a blazingly fast turnaround time by scientific standards.
Also, we’re in the earliest days of genetic medicine. We can be sure that every academic lab and pharma company are pouring money into improving these techniques and broadening their reach. Gene editing is only going to get better, cheaper and easier. Another experimental approach, called prime editing, may be able to make more precise changes than current CRISPR therapies are capable of.
If this promise is borne out, we’ll soon be able to cure other terrible diseases, like progeria or Tay-Sachs, at the root. We can expect to see a day—perhaps not as far off as we think—when genetic editing will be routine. When that day comes, our health will be fully under our control, rather than the whims of fate, and genetic disease will be a thing of the past.