Many of us will have heard of genetic medicine and gene therapy but do we really understand what it is and where it’s going? Able spoke with Dr Janet Allen, Director of Research and Care at the Cystic Fibrosis Trust, an organisation that has been supporting gene therapy research for over 10 years, to find out more.
The words ‘gene’ or ‘genetic’ are still mysterious to many of us. We have a vague notion of what they mean, so I started by asking Janet to outline just what gene therapy means.
“Gene therapy is a way of treating conditions in a broad sense, where you have a genetic defect such as a mutation in a gene and the idea is that the gene therapy delivers a normal gene into the cells. That then allows that gene to create the normal function for the cells,” Janet tells me before making an important distinction regarding how different forms of gene therapy are used in the treatment of other conditions.
“Gene therapy is also used in slightly wider terms to treat cancer. For cancer treatment, really what they’re doing is modifying the way that the immune system attacks the cancer. The two things are slightly different”.
Our conversation occurs at a tantalising time. The CF Trust has just finished a phase two clinical trial – the largest ever undertaken in gene therapy and are currently analysing the data for publication in October. The trial was ‘double-blind’ against a placebo meaning that neither the patients, nor the doctors giving the therapy, knew if they were actually using the drug or not. The staff and 120 patients will therefore only find out whether the drug had any discernable benefits in the autumn.
We tend to think of genes and things like DNA as part of our permanent identity just like the shape of our nose and not likely to change; so are the new genes also permanent?
“Yes and no,” guides Janet. “It depends upon how you deliver the gene. If you deliver the gene in certain vectors it will only last in the cells for a certain length of time, whereas if you deliver the gene in other vectors, such as virus vectors, it can get lodged into the cells permanently”.
The trial that has just taken place did not deliver the gene via a virus vector which might sound odd but there are good reasons, as Janet explains: “(The gene used in the trial) doesn’t integrate so the trial that was running was giving the gene every month, specifically with cystic fibrosis patients through a nebuliser, into the lungs”, Janet confirms before explaining further: “A lot of viruses survive by what’s called integrating. They integrate into someone’s DNA and those viruses can be used to deliver gene products.
Gene therapy was developed several decades ago and it was used principally, initially, for children that are born without an immune system and who have to live in a ‘bubble’. They were referred to as the ‘bubble kids’ and they basically have no mechanism for fighting infection. It’s known by the abbreviation ‘SCID’: Severe Combined Immuno Deficiency.
For those children, they were delivering the gene in viruses but in one particular patient it caused problems. It started to divide with the cells and it developed into a tumour.” Of course after this point, research methods were heavily scrutinised and it was clearly felt that delivery through a virus vector was somewhat riskier (though more efficient) than other methods, hence the use of the current technique.
Keeping It Safe
Janet tells me that “There was a big moratorium on further studies but the vectors are now much better and they can target where they’re going to so they’re much, much safer than they were then. As with all science, people went in with the best intentions and things that were not particularly good happened; people went away, thought about it, and have come up with much better systems now”.
Fortunately, there are other delivery methods available: “One of the issues with gene therapy is getting the gene into the cells. Cells are very good at keeping gene products out. So what they’ve done is wrap the gene up in fatty particles called liposomes and that allows the gene to be taken up by the airway cells. It’s quite an efficient process but if you could put it into a virus it would be a much more efficient process because viruses are designed to get into cells.”
In science, an experiment (or trial) will always provide outcomes, even if they aren’t always what was expected or desired. ‘Success’ is a difficult word to pin down but Janet seems to have her personal view nevertheless, saying: “Success would look like an improvement in lung function. For somebody who has CF it would be independent of the nature of the mutation that caused the CF in the first place so that is an advantage over and above only a particular subset of people responding. Any treatment is going to need multiple doses and is going to be lifelong and none of these treatments is going to be what you might call a ‘cure’ so it’s going to require long term treatment – but if you get an improvement in lung function that’s worth it”. Or in other words: some kind of general improvement across different CF mutations, rather than merely showing efficacy for patients in just one of them.
The Next Steps
This really leads to the question that all patients with a genetic disorder, especially for those with related disabilities, would like to ask. The question that asks why, when we hear about progress in the news and so on, do we not regularly see new types of drugs on the pharmacy shelf.
“We’d like to see something ‘bottled’ and on the shelf but it would always be by prescription through a doctor. The way that I see it is that CF is a quite complex condition and I think we’re beyond the stage of thinking that there’s one single magic bullet. I try to look at it as if we’re trying to create a toolbox of different types of treatments. Some will suit some patients and some will suit other patients. It may well be that we need combinations of different types of treatments in order to make the best possible outcomes for people with CF of which gene therapy would be part of that armoury. I sincerely hope that the trial is positive and we can take it forward.” Again, perhaps we have to stop thinking in terms of ‘blocks’ labelled by disease and start thinking in microscopic terms relating to things as small but significant as individual genes.
So what is it about gene therapy that gives the CF Trust faith enough to keep funding research in the area? “The work that’s been done by the Gene Therapy Consortium has been absolutely pioneering. Delivering a gene to the lungs has never been done before and they’ve encountered difficulties as they’ve gone along and they’ve had to deal with those difficulties. One of the difficulties is that the lungs are primed to get rid of foreign bodies; when you’re breathing, you take in particles from the air all of the time and your lungs are set up to get rid of them. They’re also set up to get rid of genes that are delivered through a nebuliser and they’ve had to work very hard to mask the gene so that the body doesn’t regard it as foreign and get rid of it. They’ve done really, really, pioneering work and it’s a great credit to the Consortium to have got to this point in running a phase two trial.
It’s also fair to suggest that gene therapy is making decent progress in other areas. As well as the work being done to tackle cancer and abnormalities of the blood, there are also incredible projects taking place to treat eye conditions, where genes are placed locally, in the eye itself, amongst others.
Gene therapy is clearly going to be an important part of medicine for the foreseeable future. It’s remarkable to think that serious genetic conditions may be sidestepped, sooner rather than later. As Janet concludes: “The next few years are going to be very interesting”.