New insight into gene therapy

Gene therapy has been used successfully to treat an eye disorder that prevents light receptor cells in the retina from capturing light.

When it comes to the application of cutting edge science to the medical field it doesn't get much bigger than gene therapy. A couple of decades ago it was hailed as the future - a radically new way of treating a range of illnesses and hereditary diseases, from multiple sclerosis to sickle cell anaemia. It didn't quite work out that way. As the years have passed, success stories have been few and far between.

Prof Robin Ali, of University College London Institute of Ophthalmology and Moorfields Eye Hospital Biomedical Research Centre for Ophthalmology, is at the forefront of gene therapy research and admits the application of the science in practical medicine has not quite lived up to the expectations. But, with improved technology and more realistic expectations, he believes many more diseases will become treatable. Results from a clinical study have also given him renewed hope.

"There are only a few examples of clinical trials in gene therapy that would be regarded as pretty much successful," he said. "Twenty years ago when the first trial started the technology was far too rudimentary to really take it to clinic and have a real prospect of benefit. "There's a much greater realism now about what is required and investigators are much more cautious about what one might expect from the application of the technology in the immediate future.

"As the technology develops I think that more and more conditions will be treatable by gene therapy. In the next five years we'll see many more conditions because the technology is improving all the time. It reflects the maturity of the field and we are reaching the stage where it's possible to achieve clinical benefit." Prof Ali has ended a small successful clinical study applying gene therapy to treat Leber's congenital amaurosis, a rare degenerative inherited eye disorder. The condition is due to an impaired gene that prevents light receptor cells in the retina from capturing light and turning it into electrical impulses that initiate sight. This leads to severe visual impairment in children and gets worse as time passes.

Prof Ali was invited by the Dubai-based Foresight organisation to talk about his findings in the city last week. "We've recently published the first set of results from a clinical trial of gene therapy for one specific form of retina degeneration that affects children who are born with very little retinal function," he said. "What we've shown is that in the first phase of this trial that we can safely deliver and inject a modified virus into patients without causing any harm, and we've also shown that we can improve the retinal sensitivity of a patient that allowed him to navigate much more effectively through a maze in tightly controlled conditions.

"You can see that before treatment he was not able to do so, but after treatment he could move through a maze much more comfortably, much faster and without bumping into objects." Although Prof Ali downplayed his research team's findings, he expressed his delight at what had been achieved so far. "What is very exciting for us is that we have a proof of principle that the technology we've been using to demonstrate effective treatment in animal models [can work in humans]. It's the first time we've moved it from the lab into patients and we've started to see that it's safe in patients and we're getting visual benefit."

The idea behind the application of gene therapy is quite brilliant. The concept involves treating the problems linked with mutant malfunctioning genes within the cells of a patient by inserting copies of functioning genes within those cells. The human body then recognises the "proper" functioning gene and begins to produce the necessary proteins to prevent the onset of the illness or hereditary disease.

The therapy works by delivering the functioning gene to the damaged cell using a carrier system, called a vector. This is usually one of a range of viruses. The vector allows the functioning gene to be inserted in the cell's genome which, in short, overrides the damaged gene. In theory, it appeared to be the perfect solution for a difficult area of medicine: treating diseases that have no available treatment. Unfortunately researchers have found problems in almost very aspect of the science.

The first problems concern the vector. Giving a virus the ability to carry a gene into a cell has continually thrown up obstacles. There are many viruses in nature that have the ability to infect humans, but that offer little or no pathogenicity. By modifying such micro-organisms scientists can retain the virus's ability to enter a human cell without causing any harm while incorporating the required gene into the viral genetic material. The fundamental problem when doing this in practice, however, is the resulting vector becomes less stable.

Another stumbling block has been overcoming the patient's immune response to the vector. Although the carrier virus itself is designed to cause no harm, the patient's body nevertheless mounts an immune response when it recognises the foreign object. Prof Ali's research suggests these problems can be overcome. "One of our concerns was that there was going to be a potential immune response to the virus. But the virus we've used is in fact not very immunogenic so humans don't mount a strong immune response to it," he said. "We also gave the patients steroids to suppress the immune system around the time of the administration of the vector. We did that because we were very concerned in case there was an inflammatory response but we were very pleased that we didn't see any evidence of inflammation."

The success of the work done by Prof Ali's team has given a boost to an area of science that has been in the shadow of other areas of investigation, notably stem cell research. There is still a long way to go, as Prof Ali acknowledged when he said: "I'd like to emphasise that it's only the start of the clinical trial and essentially this was a safety study. The fact that we saw any evidence of benefit in advanced stage patients is hugely encouraging because it's now a matter of treating younger patients with a much better prospect of benefit and also optimising the protocols in terms of dose and perhaps in future studies optimising the promoter sequence we use and modifying the virus vector itself to make it more effective."

Prof Ali believes gene therapy is now moving into a new era of its history, and one that will bring real results. "It's taken 15 years to get to this point and I think we'll see that now technology and the application will accelerate because it was very difficult to get to the point where we felt confident regulatory authorities were comfortable with us testing these particular viral vectors in humans for the first time," he said.

"It has taken a long time to mature but there are certain indications that it will work really well." Peter Donnelly is a Science Correspondent for the Life Science Division at IIR Middle East