Getting gene therapy into cells

Gene editing is an exciting technique that opens the door to new approaches for gene therapy - manipulating genes in the body to treat disease, either by fixing a defective gene or by adding in a functional copy of a broken gene. To find out more about the latest progress in gene therapy, Kat Arney spoke with Michael Linden, a former professor of virology who left academic research to become vice president of gene therapy at the pharmaceutical company Pfizer.

Michael - There are many rare diseases out there - six to eight thousand rare diseases - some of which have been very well characterized and the characteristic of many of these diseases is single gene defects. What that means is that the gene has a wrong instruction, in essence making a product that is either wrong or not making a product that a cell needs and therefore, we get sick. And what gene therapy is trying to do is to replace that function.

凯特- So we know that our genes are made of DNA. That’s the instruction our cells use. But you can’t just like stick DNA in people or feed DNA to people. How do you get these fixed or these ‘well genes’ into people and into the right places in people?

Michael - So, what we do here is we really look back into nature and we looked there, what we find is a concept that does exactly that. And the concept is called viruses. So viruses don’t do anything but deliver their genetic material to their respective hosts for example to us and then replicate there.

What we’re now doing is we’re taking these viruses and changing them. We’re changing them, we’re taking out the ability that they can amplify themselves and hurt us, for example. And we’re replacing the genetic material that the virus otherwise would have brought to our tissues by therapeutic DNA.

凯特- And what sort of viruses are these, because there are lots and lots of viruses that infect humans? There's everything from HIV through to herpes viruses, and all sorts of things. What were the viruses that gene therapists like to use?

Michael - Yeah, what you’ve just done is you’ve described pretty much the early stages of gene therapy development, because every single virus that we had some idea about was explored for the possibility of delivering genes to humans. Currently, the front runners in gene delivery of viruses for example, adeno-associated virus which clearly is a human virus and a non-pathogenic human virus. What that means is even the wild type virus doesn’t make us sick.

凯特- So we just catch it and nothing happens.

Michael - We just catch it and nothing happens until we’re infected by a nastier virus for example, herpes or adenovirus. And then AAV, adeno-associated virus, starts replicating and killing these cells. So for us potentially it’s even a protective virus. So, we’re taking that virus and we changed the genome to contain whatever therapeutic treatment we need and then manufacture these recombinant viruses ultimately as a drug product.

凯特- I guess the big challenge is, you’ve got this virus, it’s loaded with the gene you want someone’s cells to make. What are the big challenges there? I guess it’s kind of hard if you want to manipulate every cell in someone’s body. How do you get enough of the virus into the right place?

Michael - Yeah. So, that’s a very good question because that’s one of the challenges that gene therapy faces. That’s really the result of many years of research which have shown us that for example, adeno-associated virus can be modified and can be modified to infect particular cells or particular organs more efficiently.

What that does in essence, it gives us a panel of viral vectors based on this one system that has preferential targeting efficiencies so we can generate viruses that are very well at infecting the CNS, the Central Nervous System, or viruses that are good at infecting the liver for example. We have now a choice of many where we can really use the behaviour of these recombinant viruses and design our approach around those.

凯特- Where are the kind of the best or the most interesting approaches for really making this work in practice?

Michael - Yeah, I think you know my pragmatic view of this is that we really have to start with simple concepts and one of the example is, for example, Hemophilia B where Pfizer has an involvement. And really, what that is, it’s a single protein that’s not functioning well, that’s not functioning at all, in fact, which leads to the bleeding deficiency of these hemophilia patients.

Now, what a simple gene therapy does in this case is the Factor IX gene that’s defecient in the hemophilia B is being put into an AAV vector and systemically delivered to the liver. What that then does is it makes the liver become a protein-factory. It reads the DNA. The DNA instructions, it generates the protein - the Factor IX protein and secretes it back into the blood circulation which then allows the patients to have normal clotting behaviour which in essence means the disease can be cured.

凯特- My two really big questions about these are, a.) Is it safe? And then b.) how much will it cost? We’ll take this one at a time because I do remember from some time ago, there was a very famous case of a gene therapy that was tried and the person undergoing the therapy actually died and it did raise a lot of questions about, is this safe? Should we be doing this? So, let’s tackle that first. What has come on since then to make these therapies safer?

Michael - Yes. So, Jesse Gelsinger died in 1999 as a result of an immune response to the viral vector that was used at that point which was based on adenovirus. Adenovirus is actually a very immunogenic virus.

凯特- It’s kind of nasty stuff.

Michael - Yes, exactly. And also, it causes a strong immune response which really wasn’t or hadn't been recognized at that point. But what I have to say that in the past almost 20 years since that, we’ve learned an awful lot.

A lot of work has been done around the safety of these vectors. We now have parameters where we can measure what the response to the delivery vehicle will be and anticipate setting the stage for a really safe trial. As you know, a large part of the clinical trials are driven by one concern and one concern only, and that is safety.

凯特- And then there’s the cost. And I know that some clinical trials have happened to test things like gene therapy in the eyes, trying to restore sight. You’re talking about the clinical trials in hemophilia, there are trials ongoing in cystic fibrosis, and we hear about things like there's basically a gene-based medicine for muscular dystrophy. And these things seem to cost so much money. Is this really a viable approach for the future?

Michael - So you’re talking to a scientist and I think it would be really unwise for you to ask me about costing of this, which is very complex issue. All I can tell you is that I know that gifted people are currently considering exactly what impact costing has, and so on and so forth.

All I know is really the science behind it, and what I can tell you is that I think what we’re trying to do is more complex than just a cost for one drug. What we’re trying to do is a novel approach which in essence can, for a long time or ultimately maybe forever, modify a disease. And if it’s forever, you can ‘cure’ a disease, and these are concepts that are novel which is why a lot of government agency, pharmaceutical companies, and so on are really now sitting down and trying to figure this out.

What is the medical, what is the health consequence for this type of treatments and they can be vast in fact, because many of the disease that we’re looking at, they’re not treatable by other methods. And you know, at some point, somebody will really figure out what is the reasonable cost of this really novel space.

凯特,这是迈克尔·林登speaking to me at the British Science Festival in Swansea last year.