Simon Waddington

In Utero and Neonatal Gene Therapy Using Viral Vectors

Simon Waddington obtained his PhD in 1999 from Imperial College London, UK. He chose to specialise in Gene Therapy Research in the same year and moved to University College London in 2005 to set up the Gene Transfer Technology Group.

Simon Waddington.2He leads a team which is focused upon preclinical models of gene and stem cell transfer, particularly for in utero and neonatal gene delivery and for monogenetic disorders of the coagulation cascade.

In collaboration with Professors Andrew Baker (Glasgow University) and John McVey (Kings College London), he elucidated the fundamental role of the adenovirus capsid in binding to liver cells. Working with Dr. Tristan McKay, he has developed an application for gene transfer whereby signalling pathways in diseased organs and tumours can be quantified continually and non-invasively.

He has served on the executive committee of the British Society for Gene and Cell Therapy for six years.


When a genetic therapy study is proposed, the researcher has to cope with lots of difficulties, such as the vector choosing process – which one is the most suitable and which one has minor immunogenic properties -, and must design strategies to face with the host immunological defenses that decrease the therapeutic efficacy.

Professor Simon Waddington leads a team on University College of London that is developing preclinical models of gene and stem cell transfer, particularly in utero and neonatal gene delivery for monogenetic disorders of coagulation cascade. Working on this scientific field has renowned importance because establishing a therapeutic vehicle to be able to act on pharmacological target is essential to get the outcomes that were previously designed.

FRONTAL: Yesterday, on your lecture, you said that once we thought that gene therapy could be the perfect solution for almost every disease but that now we know that this is not perfect for all of them. What do you mean when you say that there are some difficulties to get there? And what do we have to do overcome these difficulties?

Simon Waddington: One of the main problems with gene therapy is to have enough vectors in order to widespread the number of treatments. The other problem is that the immune system is still going to track the vector, and that is what happened with hemophilia in early clinical trials, back in 2008. Patients receiving a vector injection started to express human factor IX, but then they developed a cytotoxic T-cell response against the capsid of the vector, and so, they destroyed the hepatocytes. In more recent successful trials, patients didn’t create immunity against the capsid and so, when they received the injection, they didn’t develop an immune response. Actually, to get a more successful therapy they would need higher concentrations of vectors, which would increase the likelihood of developing immune response. There is still the problem with the vector spread and the immune response against the vector. These are problems which still need to be worked on. We should be concerned on the efficacy of the vector.

F: On your paper Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer, it is proposed that human coagulation factor X binds to an hexon, which is a major viral coat protein that contributes to viral infection. What are the implications of this finding and how can it help gene therapy?

SW: In human beings, adenovirus tends to get locked up by complement proteins and tends to get absorbed into red blood cells – you don’t get a lot going into the liver. Plus, adenovirus is very unlikely to be used in large quantities for intravenous administration, because it is quite immunogenic. Other research groups, who looked up at the implications of this factor X-hexon interaction, suggest that the virus coats itself with factor X, protecting him from immune attack – it uses the proteins as a shield. I think the implications of this on gene therapy is that different viruses actually give different vectors, which interact with the host proteins in different ways, thereby affecting their tropism and ultimately their ability to infect the cell. What I think it really tells us is that we have got a lot to learn about the basic biology of the vectors that are now used for clinical applications. There’s a lot basic research to do as well as translational research.

F: So, this research also implies that the adenovirus, if in its nature form, can protect itself with the factor X, and that also means that, using it as vector, we could protect ourselves from immune reactions against the vector?

SW: One of the members of our collaborative team published a paper on gene therapy research, very recently, showing factor X interactions shield the adenovirus against certain anti-hexon antibodies. I think that a better way of avoiding immunity is possible by identifying the major antigenical epitopes on the viral capsid and then mutating those – therefore you avoid it. And, of course, a strategy I consider to be very important is to go in early enough, so that the patient’s immune system doesn’t witness it and it doesn’t create an immune response against any type of hexons.

F: We have talked about diseases that are heritable through genetics, but what can be done with those virus in other pathologic conditions, such as diabetes?

 SW: I won’t answer on diabetes, because I know nothing at all about it [laughs]. Where I work, gene therapy is for genetic diseases but, of course, the majority of clinical trials are now taking place in single genes disorders, as in cancer. There, of course, you are again looking for vectors, whether you are trying to evoke an immune response against the cancer cells, or trying to kill the cells by some form of apoptosis. The entire field of research uses different vectors, it has different goals, different genes, quite often using selective replicating virus. In other words, the vectors that cancer gene therapy use are much closer to the virus they derive from than those used for single genes disorders. Another area of research is cardiovascular diseases. One major problem in vessel transplants is that, when you put the vein graft, the walls of the vein thicken, and you get stenosis of the vessel. It would be ideal if you could provide some means of stopping the vessel from stenosis, and this is what Andrew Baker, a senior author in Gene Therapy, is looking into, using adenovirus to modulate fibrotic stenosis.

F: You mentioned earlier that cancer is a big issue for Gene Therapy. In your opinion, what are the types of cancer Gene Therapy is more focused on?

SW: I don’t think Gene Therapy is focused on anything on any particular cancer – all cancers are being researched. In Gene Therapy, there are differences between solid tumors and blood cancers. In solid cancers, we can inject directly the suicide genes into the tumor. As far as blood cancers are concerned, one of the successes seen in the clinic, with a lymphoma, was the genetically modification of T-cells to recognise cancer cells. I know that  there was complete remission of the lymphoma in two patients, and it was so quick they actually suffered from tumor lysis syndrome for 24 hours, because the tumor was being killed straight off.

F: Do you believe that  we are now in a Personalised Medicine era?

SW: The area I particularly work on is heritable child diseases. The question is – how do you prepare yourself to research in order to treat their diseases? You are going to think about treating diseases whose incidence is low when hospitals have hundreds and hundreds of patients who have their individual rare diseases. What you need here is to have a freezer full of vectors, which are essentially personalised vectors for each rare disease. I think this is the way it will eventually happen. Although we are not quite at the stage when we actually treat the mutating gene itself, this may actually be coming – we will have gene correction as well. I think we are now closer to that era.

F: But will this kind of treatment be available in worldwide terms?

SW: I always thought that Gene Therapy would actually be of no use to developing countries. So let’s take the example of Gaucher’s Disease type I. These patients suffering from it are treated with intravenous injections with glucocerebrosidase and the management of this treatment is very expensive, about a hundred or two-hundred thousand dollars a year. In the Western world, this can practically be afforded by any patient, but in developing countries, they get no treatment at all. One of the actual discussions is whether a less expensive treatment could be bone marrow transplant, for patients in India. Possibly, there’s no other treatment there and a bone marrow transplant in India costs ten-thousand dollars – a tenth of what it costs in the UK. Something like bone marrow transplants or gene modification intravenous injections therapy may ultimately turn out to be the way to treat developing countries first and then the rest of the world. This mode of thinking is coming more from the clinicians than from us, the scientists.

Interviewers: Joana Moniz Dionísio, Gabriela Andrade

Writers: Joana Moniz Dionísio