Thalassemia Cured with Gene Therapy (So Far)

After 40 Years, Gene Therapy Finally Starting to Deliver Results

October 1, 2010

Scientists may have finally cured a genetic disease using gene therapy. Three years ago, a patient with a blood disease called beta-thalassemia got gene therapy. Today, he no longer needs his monthly blood transfusions.

If everything keeps going well, it could mean that the promise of gene therapy has finally come true. And after 40 years of trying, it's about time.


Putting a working
hemoglobin gene into
the blood stem cells
of a patient with beta-
thalassemia cured him.

Many genetic diseases happen because of "broken" genes. The idea behind gene therapy is pretty simple in theory. Scientists try to put a working version of the broken gene into the patient's cells. The working gene makes up for the broken one, and the disease is cured.

For example, beta-thalassemia happens when a gene for making hemoglobin is broken. Hemoglobin is made in red blood cells and is what carries oxygen in the blood.

People with severe thalassemia depend on blood transfusions to give them working red blood cells. A type of bone marrow transplant has been used to try to cure thalassemia, but it's hard to find compatible donors. And even if a donor can be found, there's still a risk that the patient's body will reject the transplant. All these problems mean that around 1 in 10 bone marrow transplants have fatal complications.

Clearly current treatments for beta-thalassemia are not great. Luckily this disease is an ideal candidate for gene therapy.

Unlike many other genetic diseases, beta-thalassemia is caused by a single broken gene. That means that scientists can fix the problem by inserting a working copy of this one gene. That's much easier than turning off a bad gene or fixing many genes at once.

Also, beta-thalassemia is a disease of blood cells. That allows doctors and scientists to more easily remove cells from the patient, insert the new working gene, and put the cells back. Putting in the new gene into cells outside the patient's body lets scientists get away with only "fixing" a few cells.

The report that gene therapy may have worked for a beta-thalassemia patient is great news for a lot of people. It's definitely exciting for other patients with the disease, since it might allow them to live transfusion-free. Not only that, but if scientists have developed a successful gene therapy system, that may be good news for people with genetic diseases such as cystic fibrosis and even some cancers.

It's also a step forward for scientists and doctors working in the field of gene therapy. It has been hard and often frustrating work for many years. Fixing human genes in live cells can be a tricky and unpredictable process and there have been a lot of problems developing the technology. This research could mean that they've finally gotten over many of those hurdles.

Using Viruses to Deliver Genes


Scientists can use viruses to get
genes into cells.

One of the major challenges of gene therapy is getting the gene into the cells in the first place. Luckily nature has provided us with the perfect tool -- viruses.

A virus can cause disease by entering a cell and taking it over. It then turns the cell into a factory for making more viruses. The virus manages this takeover by forcing the cell to use the virus's genes.

A family of viruses called retroviruses work by inserting their genes into the cell's own DNA. If human DNA is a cookbook, retroviruses sneak in extra recipes.

Often the cell can't tell the difference between virus genes and its own genes, so it starts turning out all the parts the virus needs to reproduce and infect more cells. And because the virus genes are part of the cell's DNA now, they get passed on if the cell divides.

For gene therapy, scientists change a retrovirus so that it doesn't cause disease. They make sure that all it can do is insert the right gene into the patient's DNA. Sounds simple, right? Not so fast"ᅵ.

A Rough Road to Gene Therapy

The idea of gene therapy was first proposed way back in 1970. So why aren't there ads for it on TV yet? The truth is, it's a classic case of "easier said than done."

One of the first conditions scientists looked at for gene therapy was SCID, the "bubble boy" disease. Because of a single broken gene, SCID patients can't make white blood cells to fight off infections. SCID seemed like a perfect candidate for gene therapy -- insert a working version of the gene and that should be that.

It turned out not to be so simple. For example, from 2000 to 2002, ten children in France were given gene therapy for SCID. The treatment was successful in that they developed a working immune system. Unfortunately there was a huge downside. By 2007, four of the ten kids had developed leukemia, a blood cell cancer.


4 out of 10 kids with
"bubble boy" disease
got leukemia from
their gene therapy.

Where did the cancer come from? Scientists can make a retrovirus to stick a gene into a patient's DNA, but there's no way to control where it will end up. There are more than 20,000 genes in the human genome. That's a lot of options for where the new gene might get inserted.

Sometimes a virus puts its DNA near a gene, turning that gene on. If that gene's job is to tell the cell to grow, then cancer can come from the gene working too much. This is what happened to the boys who got leukemia after gene therapy for SCID.

Cancer can also come from a gene not working enough. If a virus puts its DNA in the middle of a gene, it can cause the gene to shut off. If that gene was keeping a cell from growing, then when the virus shuts it off the cell could start to grow uncontrollably. In other words, the cell would turn cancerous.

Another problem with gene therapy was revealed in 1999. This one has more to do with the virus than the location of the gene.

The human immune system is all about finding and destroying cells infected by viruses. It can't tell the difference between cells with a flu virus and cells with a helpful gene therapy virus. In 1999, an 18-year-old patient in a clinical study died of a massive immune response to the gene therapy virus.

Patient health is obviously the most important hurdle to get over, but there are plenty more technical problems with the idea. For instance, how can scientists make the gene therapy last? Since all cells have a natural lifespan, the ones with the inserted gene will eventually die off. That means the patient will have to have many new courses of gene therapy.

And there's always the problem of diseases caused by the failure of several genes. Gene therapy for that kind of disease would require putting in working versions of all of them.

But scientists continue their work, trying to overcome these problems and fulfill the promise of gene therapy that has kept them busy for four decades. This new study is still in its early stages, but it definitely could bode well for people suffering from thalassemia.

More Information

Stem Cells: Not Just Embryonic!


Stem cells can become
many other kinds
of cells.

In this trial, scientists used a type of retrovirus called lentivirus to deliver a working hemoglobin gene. But they didn't try to overwrite the broken gene in red blood cells. Red blood cells don't divide, so they would have to fix millions of them and then put them back in the patient. And they'd have to do that over and over, since red blood cells typically only live for about 100 days.

The trick these scientists used was similar to what they did in the SCID study. They put the genes into a different kind of cell: the hematopoietic stem cell (or blood stem cell).

The term "stem cell" can set off alarm bells in people's heads, but there are lots of different types of stem cell in the body. There's way more to stem cells than the embryonic kind that everyone fights over.

Most cells in the body have an identity that they're stuck with. Red blood cells, muscle cells, and nerve cells can never become another type of cell. But these grown-up cells weren't always grown-up -- they started out their lives as stem cells!

Generally, a stem cell is one that can become any one of many different types of cell. It develops an identity based on signals it gets from its environment. There are muscle stem cells, neural stem cells, blood stem cells and more!

Blood cells come in a lot of different varieties. Red and white, for instance. Even among white blood cells there are many different specialized types of cell. But all those cells came from blood stem cells.

Blood stem cells are found in bone marrow. They divide and make copies of themselves so that there's always a pool of stem cells. Then some of the daughter cells from those divisions develop into working red or white blood cells.

These scientists took blood stem cells out of the patient, used a lentivirus to insert a working hemoglobin gene, and put the stem cells back into the patient. There was no worry that his body would reject the transplant, since he was just getting his own cells back. And they didn't need to worry about his immune system responding to the virus, since the gene had already been put in the cells outside of his body.

The "fixed" blood stem cells got to work, producing all sorts of different types of blood cells. Most of those don't use the hemoglobin gene, so they weren't affected by the gene therapy. But the red blood cells that grew from the fixed stem cells were able to make working hemoglobin. So the patient doesn't need his monthly transfusions anymore!

Remaining Challenges

There were actually two patients at the beginning of this study, but only one was successfully treated. The other patient's stem cells weren't able to establish themselves back in his body after being fixed by scientists in the lab.

The scientists believe the problem was somewhere in how the cells were handled. Stem cells can be pretty tricky to work with, and any mistakes could cause the whole procedure to fail.

Another issue is related: there was only one patient in this study! It's definitely impressive that gene therapy seems to have worked for him, but the technique needs to go through a lot more testing before it's commonly used in hospitals.

Also, scientists still don't know how to control where the virus inserts the working hemoglobin gene. One potentially worrisome thing about this current study is that the new gene ended up in one specific place more often than they expected. It's an odd result, since it should be pretty random. Scientists are concerned that it could mean that the cells with that particular insertion site grow more than others. Fast-growing cells could possibly become cancer.

It's only been 33 months since the patient got his transplant of fixed blood stem cells. But he's been transfusion-free for the last 21 months, and there's no sign of cancer development or other negative side effects. For now, scientists are watching him very carefully to see if his blood stays healthy long-term. After all, they want to be pretty sure before they claim victory.


Robin Trujillo

Another gene therapy example that worked. And it has a cool part where they stick a needle in someone's eye.