Using Genes to Fix Inborn Errors of Metabolism
Diana - Gene therapy may help in the treatment of what are known as in-born errors of metabolism, where part of a biochemical pathway is faulty or missing and this can lead to a build-up of toxic waste products inside cells, damaging their functions. Professor Tim Cox is from Addenbrooke's Hospital in Cambridge where he works on these diseases and is developing new ways to treat some of them. So Tim, tell me what these diseases are.
Tom - Well thank you. I mean, these are pretty severe diseases and we've taken a rather tough route to try and deal with them. They affect principally the brain, so these are neurodegenerative disorders that damage the neuronal cells and cause a compromise of the person who is unfortunate enough to inherit rare defects that cause them. So, typically, in the case of Tay Sachs disease, which is almost an iconic disease, emblematic of this whole class, the child is a beautiful child usually, born quite normal. But after a few months of life, starts to develop neurological difficulties with weakness, not able to sit up, problems with sight, swallowing, coordination, and it's a very progressive condition indeed. They often go blind and nearly all the children with this particular condition die in the first few years of life. We've seen quite a few patients over the last few years referred and it's quite clear that although in some populations this particular one is screened for, it still occurs, and it's no respecter of belief, ethics, or anything else.
Diana - And what other diseases do you work with? Metabolic related ones?
Tim - We work on Gaucher's disease which is a condition, an inherited condition, that principally affects the blood system, the liver, spleen, and the blood system very much like Professor Thrasher was telling you about earlier. But for that, there are alternative treatments in many cases, so you can provide the missing protein, which is an enzyme that can be targeted to the cells that are deficient, having a little address on it that's posted through the letter box of the cell membrane to deliver the corrective force, the corrective factor. But for the brain, it's a little more difficult and those are the ones that we've chosen the latter phase of our clinical research to try and tackle now because it's going to take a lot of work.
Diana - So what have you done to explore new ways of treating Tay Sachs?
Tim - At a risk of getting a bomb under my car, we've had to use an authentic model that can occur - two authentic models that occur - in experimental animals. Though I'm probably taking risk in saying this, I'm quite happy to do so because I'm clear that the reason for doing it is proper. So there are spontaneous models that occur in large animals, in cats, and sheep actually, and also in flamingoes, though they're a bit difficult to work on. But also you can generate these through the wonderful work of Sir Martin Evans, who got the Nobel Prize a few years ago for being able to develop targeted mutations in a controlled way, in experimental mice particularly. Those animals that have this defect really develop a very severe disease, a very acute disease and have to be killed under humane conditions when they're about 118 days old. But with one dose of gene therapy, using a different vector system from what
Professor Adrian Thrasher was mentioning, we're able to, with a single treatment, have those animals survive to the 2-year span which is allowed for a laboratory mouse, and our colleagues in cats have had similar results in the United States. You can't work on cats easily in this country as you realise.
Diana - So how is the vector different in this case then?
Tim - Well it's a different vector. The virus is called the adeno-associated virus, a very tiny little genome and by putting in the proper expression motifs and the correct sequences, you can get expression of what we refer to as "household genes", that are needed to deal with the material that accumulates in Tay-Sachs, Gaucher's, other related conditions. The great advantage of this class of disorder, although they're absolutely horrible, is they do have a particular property in that it's possible to provide a factory, a little source of the corrective factor, in one small part of the brain which then diffuses this out of the corrected cells locally right throughout the brain and is distributed to where it's taken up - a sort of secretion recapture pathway. This is a very remarkable way of complementing a whole tissue, a massive super computer, which is how I think of the brain (other people's anyway!). It can correct it in a wide field. That's really, in a sense, the beauty. A terrible disease but there's a little trick of nature which you can exploit for therapeutic purposes.
Diana - So how far away are you from clinical trials and actually putting this into practice?
Tim - Well, I'm only 4½ million Pounds away! But we have applications in to the European Union and to government bodies in the UK at the moment, and - having done a great deal of work - in combination now we hope with a commercial outfit in Europe that we hope will be able to grow the GMP, the Good Manufacturing Practice safe vector, with all the toxicity done for human use. We hope very much in a year or two to actually start the first trials in this condition.
Diana - Well, I hope your funding proliferates just like your description of the healthy cells. That's Tim Cox and he's from Addenbrooke's Hospital. Thank you very much.