New treatment for sickle cell disease?

Sickle cell anaemia is an inherited blood disease. About a quarter of a million children are born with it every year and they suffer low blood counts, joint and bone pain as well as other health difficulties. At the moment treatments are quite limited, but now a team at the University of California, Berkeley, have developed a technique to genetically edit the bone marrow cells that produce the affected blood cells and fix the problem. So far they've proved it works in a dish and also in mice given human blood cells. Researcher Mark DeWitt told Chris Smith how...

Mark - Individuals that have sickle cell disease produce red blood cells that have an abnormal or sickle shape and these so-called sickle red blood cells can clog blood vessels. And in so doing it can also cause chronic pain, organ failure, pulmonary hypertension so individuals that have the disease have a dramatically reduced quality of life. And even in developed countries like the U.K. or the United States, only live until about an average age of forty.

Chris - How is the disease managed if someone presents with sickle cell disease - how do we look after them?

Mark - Individuals with sickle disease are often managed using blood transfusions, so you transfuse healthy blood to replace the sickle blood. There is a pharmacological intervention, hydroxyurea, which has serious side effects but can reduce the manifestations of sickle disease. There is a treatment for the disease and that's a bone marrow transplant.

Chris - And how does that work?

Mark - The same as if you're getting a bone transplant for leukemia. You find a suitable bone marrow donor and you what we call ablate, or basically kill off the bone marrow in the recipient and then you take bone marrow from a healthy donor and infuse it into the recipient. And so you, basically, you get new bone marrow and then you're effectively cured.

Chris - The rationale, of course, being that the new bone marrow doesn't have the genetic problem that makes sickle cells disease which is why the people are better. But it's obviously a very radical step to take isn't it, with a lot of risk attached so what are you trying to do instead?

Mark - We're developing methods to correct an individual's own bone marrow. We know exactly the nature of the mutation, we know exactly where it is in the genome. The sort of idea is that we would take the bone marrow out from the patient, you would correct it using the technology called CRISPR-Cas9, and then you take the corrected bone marrow and put it back inside the patient.

Chris - How practical is this - do you think that you could treat enough cells and edit them in this way to put the gene right and then get enough of them back into the patient to make the disease symptoms go away?

Mark - We think that we can. One only needs to correct a small minority of the bone marrow for the patient to be functionally cured of the disease because the healthy cells will outcompete the diseased cells in your blood and in your bone marrow.

Chris - So what evidence have you got that this is going to work?

Mark - What we did in this study was we obtained bone marrow cells from an individual with sickle cell disease and then we corrected the mutation using CRISPR-Cas9, and then we confirmed that they appeared to be healthy; they produced significant quantities of adult hemoglobin, and then engrafted the edited cells into a mouse model. The edited cells can successfully engraft in a mouse and persist over a period of four months and this tells us that the edited stem cells are viable for a transplant type procedure.

Chris - Indeed, that you haven't rendered them unhealthy that they can survive and, presumably, were they to do into a patient they would have a good prospect of finding their way to the bone marrow and then setting up the production of fresh, healthy red blood cells that could make up for the problem the patient previously had?

Mark - Correct.

Chris - So how do you actually do the edit process, as in once you've got those cells in a dish in front of you - how easy is it to do this genome switch to get rid of the sickle cell change and render the cells genetically healthy?

Mark - It turns out it's actually quite easy. The way we do it is we take purified Cas9 protein and we mix it with this thing called a guide RNA, which is exactly what it sounds like, it's a little piece of RNA that guides the Cas9 protein to the the sickle mutation inside the cell's genome. We also provide a short piece of DNA that programmes and edit; in this case from sickle to wild type. Cas9 makes the cut, the short piece of DNA past in and voila - it's all fixed.