No one person had been definitively cured by gene therapy, Professor Ian Hart (Richard Dimbleby professor of cancer research, Guys, Kings and St Thomas's hospital, London) told pharmacists when he delivered his part of the 2000 Penn lecture.
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Ian Hart: Science of the future |
Clinical success had yet to be shown but there had been some interesting results. "We know we can modify cellular behaviour in a petri dish but the biggest problem is changing behaviour in vivo," he said. Once the problem of delivery had been "cracked" then gene therapy would come into its own.
A good candidate for gene therapy was malignant melanoma, which once it had metastasised was essentially incurable, said Professor Hart. One approach to such gene therapy was "in vivo vaccination." It was possible to grow the tumour in vitro and insert copy DNA that would encode for "something that stimulates the immune system." Another approach would be to use drug resistance genes. By inserting such genes into stem cells it would be possible to give higher doses of chemotherapy without killing off normal cells, explained Professor Hart.
However, these approaches had problems as they were considerably labour intensive. Patients had to supply cells to be grown ex vivo, which were then modified and eventually put back into the patient. Such procedures took time, so much time that the patient could have advanced to a terminal stage in their disease.
Professor Hart went on to describe several different approaches to the delivery of gene therapy. As gene therapy vectors, plasmids provided poor transfection efficiency with no targeting or specificity. Retroviruses had the advantage of being integrated into dividing cells, which guaranteed long term expression. The chance of insertional mutagenesis was a disadvantage of using retroviruses as vectors. Such vectors might insert anywhere in the gene, "knocking out" or "switching on" specific genes which could lead to cancer. The advantageous "long term expression" would also result in more chance of long term toxicity, warned Professor Hart.
Adenoviruses had been thought of as safe vectors for delivering gene therapy but the recent death of a patient in the US, with a non life threatening disease, had brought them into question. They also induced a strong immune response in patients and so were unsuitable for repeated use, he said. Viral vectors had already been employed in gene therapy clinical trials and a report appearing in Nature Medicine in August [see page 187] would show some efficacy for gene therapy in patients with brain tumours, said Professor Hart.
Describing the critical areas for future development in gene therapy, Professor Hart warned that scientists would have to attempt to improve viral vectors or to develop non-viral vectors. It was also vital that vector targeting and specificity was improved.
"Gene therapy is unlikely to be a panacea for all cancer types," said Professor Hart. It was very much in its infancy, but in 25 years time gene therapy would be an accepted part of an oncologist's treatment options. "The people who follow you as pharmacists will have to deal with these issues," he told the meeting.
Responding to a statement from the audience that more genetic changes took place through natural processes than through genes being inserted, Professor Hart agreed and said of somatic gene therapy: "I have as few concerns with using this approach as using small molecules to get rid of headaches." The public's perception of genetically modified crops highlighted the difficulty society had in accepting these issues.
Another audience member raised the issue of contamination and handling of gene therapy products. Professor Hart agreed that pharmacists would need notice to deal with gene therapy products and warned: "In the life of this audience, pharmacists will be handling gene therapy products" so it was essential to plan for this now.
Professor Hart concluded by reminding pharmacists to look at the big picture: "Gene therapy promises a lot, but to date hasn't delivered a lot."
Addressing the ethical perspective of gene therapy, Ms Susan Bull (deputy director, Nuffield Council on Bioethics) focused on the arguments raised in discussions about gene therapy. She stressed that the opinions expressed in the lecture were her own, and not those of the Nuffield Council.
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Susan Bull: Society already affecting the gene pool |
Ms Bull used the recent case of a teenager in the US, who died after being treated with gene therapy, to illustrate some of the issues raised by the practice of gene therapy, even after thorough ethical review.
The case involved the treatment of liver disease in which a modified adenovirus was used to correct ornithine transcarbamylase (OTC) deficiency. In its severe forms, the deficiency caused death in infancy but those with a mild deficiency could survive if they followed a strict diet and drug regimen.
An adenovirus vector had been developed that could lead to in vivo gene expression within 24 hours, which was crucial for treating the acute phase of the disease in newborns. A different vector could then be used for ongoing treatment, or a liver transplant could be performed.
However, the initial trial protocol involving treatment of newborn babies was changed after being considered by ethicists who argued that, as the trial was designed only to test toxicity, it would be preferable to begin with adult volunteers. The bioethicist involved had argued that it was wrong to do such non therapeutic research on an individual who could not consent. After discussion with patient groups, the researchers agreed it would be better to treat adults. Ms Bull pointed out the difference in terminology used by the bioethicist, who used the words: "non therapeutic research", and researchers, who talked about "treating".
The trial continued until September 17, 1999, when Jesse Gelsinger, an 18-year-old with a mild form of OTC deficiency and the eighteenth patient in the trial, died. The inquiry that followed Jesse's death raised concerns both about safety issues and issues about consent and whether sufficient information about risk had been given to the volunteers.
Ms Bull went on to talk about the ethical issues raised by the possibility of germ-line modification of humans. As far as she was aware, genetic modification aimed at intentionally altering the germ-line was not permissible in any country.
It was widely argued that germ-line therapy currently offered too great a risk to both the individual and society for it to be ethically acceptable. If, however, the science was sufficiently advanced to conduct the first human trials, were there ethical considerations that would preclude such research taking place?
Arguments against permitting germ-line modification for medical purposes included the fact that it was not necessary and amounted to "playing God". However, society was already affecting the gene pool by aborting children, by selective implantation and by treating diseases that would otherwise cause death, said Ms Bull. "We are consciously adding and subtracting genes from the gene pool all the time," she said. If somatic gene therapy could be justified as being in the best interests of a foetus, and if safety concerns about the use of germ-line therapy to cure the same disorder had largely been answered, what justification was there for saying that in utero somatic cell therapy should be carried out in each generation, rather than eradicating the condition by germ-line therapy?
Concerns had also been raised that if germ-line genetic modification was permitted, this might be used for increasingly frivolous forms of genetic enhancement, reflecting current fads in society, and it had been suggested that children might end up inheriting the genetic equivalent of flares and a large gold medallion, said Ms Bull.
It had been proposed that two different approaches to germ-line engineering in humans could be used - these were homologous replacement and the use of artificial chromosomes. Artificial chromosomes could be engineered to carry the desired genes into the cell, and it had been suggested that these could be designed so that they were not inheritable. It had also been proposed that the choice of future generations could be protected by putting a biological lock on the new gene so that a hormone pill or other activating substance had to unlock the gene, before it could be expressed.
Ms Bull went on to ask where the line should be drawn between what amounted to treating a disease and what amounted to enhancement? Examples at each end of the spectrum were easy to distinguish, but it was more difficult to distinguish between a minor disease and a cultural inconvenience. The argument in favour of genetic enhancement was quite simple, said Ms Bull. Why would people not grab the opportunity to make their children taller and more intelligent?
Society would welcome any educational breakthrough that improved the mental capacities of students, it had been argued, so why should the same ends not be achieved through genetic technology? "If medical technology is used to enhance our appearance and weight, is it morally unacceptable to achieve the same ends using germ-line genetic engineering?"
It had been suggested though that while enhancing intelligence might be a humane aim, its successful realisation might have profound implications for the understanding of just what it was to be human.
Ms Bull quoted Lee Silver, a biologist at Princeton University in the US, who had suggested that a century or two of widespread engineering might even create a new species of human, no longer willing or able to mate with its "gene poor" relations.
Ms Bull directed pharmacists who wished to refer to the council's work to its website (http://www.nuffield.org/bioethics). Although the council had not considered gene therapy per se, its reports had considered ethical issues relating to gene therapy where these were relevant.