Gene Therapy to Treat a Defective Immune System

Chris -    An important group of diseases are those that occur when a person inherits a defective form of an essential gene, and this can cause tissues and organs to fail.  Historically, there's been very little that could be done to cure people with this sort of problem.  But now that's changing and a number of techniques exist to help people who suffer from some of these sorts of disorders.  One of the pioneers in this field is Professor Adrian Thrasher.  He's from Great Ormond Street Hospital and he's with us.  Hello, Adrian.

Adrian -   Hello.

Chris -   So first of all, tell us what sorts of diseases you're looking at.

Adrian -   We're interested in patients who are born with inherited defects of their immune system.  So I guess the most familiar one to many people was the so-called "bubble babies" who were born without any immunity and who were very susceptible to common or garden viruses.

Chris -   What causes that to happen?

Adrian -   There are key genes that are involved in the growth and development of the immune system and if these genes have mistakes in them, mutations in them, then the immune system doesn't develop properly.  So, these patients are often born without any lymphocytes, for example, that fight infection.

Chris -   The white blood cells.

Adrian -   Right.

Chris -   So, is it fairly easy to identify what the gene is that's causing that?  Presumably, this is not a whole cluster of genes that are affected at once? This is a single gene which goes wrong which then causes those people to have that problem.

Adrian -   Yeah, that's right.  Ten years ago we knew of a couple of genes that cause this type of disease, but now we've identified most of them.  There are still a few out there to be identified, but we can pretty much identify the defective gene in the majority of patients now.

Chris -   But when a person has this disease, have they got just one gene which is not functioning, or have they got a range of genes at once which have gone wrong?

Adrian -   Again, it's variable. For the classical, what we call primary, immunodeficiencies then it's usually just one gene that is defective.  But undoubtedly, there'll be more complex immunodeficiencies where several genes will contribute to that disease.

Chris -   So how are you trying to solve this problem?

Adrian -   Well, over the last 40 years we've understood that a bone marrow transplant is a very effective therapy for these diseases.  So if patients have a good donor, within the family for example, we'd expect to cure these children very effectively.  The trouble is if the patients don't have a good donor - and for those children the risks of transplant are considerable. So we, and others, have been trying to develop gene therapies which will be more effective and also safer.

Chris -   I think that was the situation that happened with David Vetter who was the American boy  who was "the boy in the bubble". A donor couldn't be found in his case.  He did end up with a transplant - I think from his sister - and unfortunately it wasn't a good match.

Adrian -   That's absolutely right.  So he had the classical "bubble boy" disease and was maintained within a sterile environment until his early teens.  He underwent a mismatch transplant and died of complications of that transplant.  Those same complications exist today because matching transplants is still difficult.

Chris -   So how does gene therapy help?

Adrian -   Gene therapy helps because we are not dependent on using another donor so there is no mismatch.  We can use the child's own bone marrow. And if we have effective ways, which we do now, of introducing correct copies of the defective gene into that bone marrow in a stable way, then in theory we can reconstitute their immunity using the patient's own cells.

Chris -   So what is the technique?

Adrian -   The technique is relatively simple.  We harvest the bone marrow from these children under general anaesthetic. The cells are then modified in a special laboratory within the hospital, and then after several days, during which the cells take up the new genes, the cells are given back to the patients.  So in fact, it's a very, very simple procedure and in some children we've been able to do that almost as an outpatient.

Chris -   So how do you get the gene that they need - the one that they have a defective copy of - how do you get the healthy working gene into their stem cells?

Adrian -   There are lots of different ways of doing that in the laboratory.  The most effective way is to use a virus, because viruses have spent millions of years evolving mechanisms of getting genes into cells in an efficient way.  We know we can modify these viruses to render them relatively safe and instead of the viruses taking their own viral genetic material into cells, they take the transgene - the therapeutic gene - into the cells.

Chris -   So you delete or remove the internals of the virus, the bit that would make more virus, put in the therapeutic gene, then you infect the person's own cells with that virus in a dish.  Does it then insert that gene into their own DNA in those cells?

Adrian -   It depends what sort of disease you're trying to treat, but, for bone marrow diseases, we want the gene to be present in all of the blood cells for the lifetime of the individual, so it has to be stable.  So, for that reason, we need the gene to be stably-integrated into the DNA of the haematopoietic stem cells - the blood stem cells - in the bone marrow.  So yes, it is inserted into the DNA which means that when the cell divides, that transgene is also copied onto the daughter cells.

Chris -   Can you control where into the person's DNA that virus adds that new healthy copy of the gene? Because presumably you've still got the old defective copy sitting there and you put the new one in somewhere else in their DNA?

Adrian -   That is one of the issues.  At the moment, it's not possible to control that in a very efficient way.  The clinical trials that are ongoing don't even attempt to do that, but we know from ongoing laboratory research that it may be possible to do that in a much more precise way and even, in some cases, it may be possible to correct the original genetic defect.

Chris -   That must carry a risk then.  If you can't control where the virus delivers its genetic cargo into the person's genome, could that cause problems?

Adrian -   Yes, and it has done.  We've learned from the first clinical trials that were initiated over ten years ago now that sometimes the transgene can affect the operation of genes that happen to be close by.  So, for example, genes that control the cell cycle, or genes that can initiate leukaemia; so there is a finite risk to this sort of technology, although the sort of trials that we're conducting now have additional strategies whereby we try and lessen that risk.

Chris -   And when you put the now healthy (hopefully) stem cells back into the person, they home back into the bone marrow, take up residence, and start to make the kinds of blood cells and immune cells that the patient originally lacked.  Do they then end up with a mixture of unhealthy cells and healthy cells, or do these new modified ones take over most of the cells in the blood?

Adrian -   It depends on the conditions.  So in some conditions, the patients are born, for example, without any white blood cells. So any new cell that comes out is obviously a cell that has a transgene in.  So in that situation, all the cells will be new functioning transgene-containing cells.  In other conditions, we know that all you need to achieve is perhaps 10% of functioning new cells to correct the disease.  And so that is what we shoot for.

Chris -   Just to finish up, Adrian.  Is this something you have to keep doing many times throughout a patient's life or is one treatment sufficient?

Adrian -   For the sorts of diseases we're treating, we're hopeful that one off treatments - the same as a bone marrow transplant - should be sufficient for the lifetime of that individual.

Chris -   How many patients have you helped this way now?

Adrian -   We've treated over 20 patients at Great Ormond Street with these types of conditions. And worldwide now I would estimate that probably over 80 patients have received this type of therapy.

Chris -   And who are probably alive thanks to gene therapy.  Adrian, thank you.  That's Adrian Thrasher from Great Ormond Street in London.