Gene editing fixes immune deficiency disease

Gene editing is being used to tackle an inherited immune disorder that leaves people with serious infections.
16 January 2017

Interview with 

Harry Malech, National Institutes of Health


This week, scientists in the US have taken the first steps towards fixing a genetic defect that leads to an inherited immune problem which is called chronic granulomatous disease and leaves sufferers prone to serious infections. The team at the NIH have used a DNA editing technique called CRISPR to correct a mistake in a gene that arms immune cells so they can kill bacteria and other infections. The team are doing it on bone marrow stem cells that produce immune cells that then circulate in the blood. The idea is to fix a patient’s own cells safely in a dish and then return them to the patient. Harry Malech explained the process to Chris Smith...

Harry - For most of my career I’ve been interested in an immune deficiency called chronic granulomatous disease. Patients with this suffer from recurrent infections because they’re circulating white blood cells, called neutrophils, fails to produce hydrogen peroxide. And it’s used by these cells that engulf microorganisms to kill those microorganisms that if you don’t have the hydrogen peroxide then the cells can’t do their job and that’s why the patients suffer from recurrent severe infections. They get pneumonias, they get infections of their bones, they can get liver abscesses and so our goal is to find a way to fix them.

Chris - Why do they have that condition? What’s the underlying process that leads to them lacking this natural hydrogen peroxide disinfectant?

Harry - This is an inherited problem. The majority of patients have a mutation in a gene carried on the X chromosome. One treatment is bone marrow transplant which can cure the disorder, but because it involves collecting cells from another person, those cells may see the new host as foreign and, therefore, one can get high risk from this disease from graft versus host disease. But knowing that a transplant can cure means that if we take the patient's own cells and fix them, we might have the same outcome but without the graft versus host disease.

Chris - So talk us through what you are actually doing then. Which cells are you working with and how are you manipulating them?

Harry - Most of our patients, we are able to treat them in a way that makes the stem cells come out of the marrow and circulate in the blood, which we collect using a large blood centrifuge, and then we use gene editing techniques to fix the mutation that’s in those cells.

Chris - And when you do this, what fraction of the cells that you started with actually get fixed?

Harry - We’re pretty excited by that fact that we’ve been able to reach somewhere in the range of 25 to 30 percent of cells being fixed in the dish. However, the critical cells are the small subset of those cells that are able to go back into a patient and then graft long term. And our other studies in mice show us that we probably get into about 10 to 20 percent of the long term cells that can restore marrow.

Chris - And having fixed at least a proportion of cells in the dish, is the goal that you will put those cells back into the person having ascertained they’re safe, of course, so that they would go back to the bone marrow and then act as long-term, long-lived supply of healthy immune cells so the patient would have enough healthy cells in order to fight off infections?

Harry - I actually don’t need to repeat what you’ve said because you are exactly correct. The goal here is that if you don’t hold these cells too long in the culture, they retain their ability to re-engraft in the patient they came from. And if you’ve now got fully corrected cells, they are able to serve as long-term, maybe even the life of the patient, to make neutrophils that now can produce the hydrogen peroxide.

Chris - Do you have any evidence that that can be achieved? Have you done the experiment where you’ve taken the cells and put them back into, admittedly not a person, but something resembling a person i.e. a mouse to see if they’re capable of doing that?

Harry - There’s a very helpful mouse model such that these mice have some defects in their immune system which allow human stem cells to be engrafted in the mice. So, from the point of view of the mouse’s marrow, it’s like a little mouse person and one can actually follow these mice out for, in the case of the paper, we followed them out for five months. That’s a long time, certainly not the lifetime of a person, but long enough for us to say with some certainty that we have corrected the long-term engrafting cells that could fix patients if we actually took these and engrafted them back into people.

Chris - Now what about the safety side of this though? Because it’s quite an unnatural experience for these cells to be in a dish, to have their DNA edited and then to go back into a person again. What are the risks and how sure are you that we haven’t introduced other changes into those cell’s DNA so they could, for instance, spawn blood cancers?

Harry - You raise one of the key safety points that many in the field, including our FDA and other regulatory agencies, are concerned about. In the paper we describe a number of sophisticated ways in which we look to see if we’ve made changes in other places in the genome. At this first pass, it looks as if we haven’t made detectable changes at other places in the genome. We believe, however, that before we were to actually do this in patients that we need to do more work in that area, both to satisfy ourselves, and to satisfy the regulatory agencies that we’ve made no untoward changes in other places in the genome.


How do you test if the person has this to confirm diagnosis?

The disease runs in families and can be confirmed clinically and genetically. It's an X-chromosome linked disease caused by a known mutation, so doctors can screen for it.

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