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you are going to be held to it. And I think that was true in the early days: people were so excited about the potential that they oversold everything. He believes such premature hype has also stymied corporate investment in gene therapy. I think our first opportunity for that has come and gone with the overselling, and I think the second one is going to be scrutinised a little bit longer, like kicking the tyres on a car, before people jump in with both feet to make this a reality.


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Gene therapy holds huge promise to treat intractable conditions. Jane Lyons separates the hope from the hype.
EIGHT, six, four, three John Forbess hopes rose as the number of lesions fell. Diagnosed with melanoma in 2007, his three operations had taken more than their pound of flesh, with the last one removing a 16inch (41cm) swathe of skin from his lower left back. But more lesions kept appearing and last February he was enrolled in an American phase III clinical trial for a gene therapy that had shown success against the deadly cancer. As the weeks rolled by, Mr Forbes, 59, watched his lesions disappear. He was declared disease-free in October. As these lesions were disappearing, I was going, wow, not only is it Gods work here but it is science working beautifully a new drug coming on that can help so many other people and hopefully save their lives, Mr Forbes says. OncoVEX, an oncolytic viral vaccine developed by a small US biotech company, BioVex, and now owned by Amgen, created

a stir when the results of its phase II trial were published in 2009.1 Administered via intratumour injection, the vaccine contains the herpes simplex virus type I, which has been modified to carry the gene encoding human granulocyte-macrophage colony-stimulating factor. It selectively targets and replicates in the tumour cells, destroying them in the process, as well as stimulating an immune response to kill cancer cells throughout the body. Out of the 50 phase II study participants with stages IIIc and IV melanoma, 10 had a complete

senior vice-president of research and development. The problem has always been finding the most safe and efficacious way to do it, and the timing for that. And our hope is that OncoVEX will be another step on that pathway and that others will [be encouraged to] continue. Decades of research, animal studies and some widely publicised adverse events are finally coalescing into success as gene therapy finally starts to deliver. Gene therapy clinical trials for Parkinsons disease, 2 Lebers congenital amaurosis,3 haemo-

whatwearegoingtoseeinfiveyears areveryclear,unequivocalsuccesses
Professor Ian Alexander
response and four had a partial response. According to Amgen, the scientific world is waiting for the results of the phase III trial, which ended in June, with great excitement. I think most scientists and physicians dont really doubt that there will be a place for using genetic material delivered to patients as therapeutic modalities, says Joe Miletich, Amgens philia4 and heart failure5 also prove a portal to the promise heralded by the human genome project. On the genome projects completion in 2003, scientists hailed its identification of 20,000 25,000 human genes as the pivotal moment of a genetic revolution. Gene therapies were to be the vanguard of a new charge on disease, whose cause and incidence

doctors would now be able to identify and predict, as well as treat. Viruses are the most common vectors used to deliver the therapeutic gene to the target cells, and these include retroviruses, adenoviruses, adeno-associated viruses and herpes simplex viruses. Since 1990, they have accounted for two-thirds of vectors used in clinical studies but other delivery systems include artificially created lipid spheres with an aqueous core, stem cells and the direct introduction of DNA into the cell. At present, only somatic cells are targeted for human treatment. Germline gene therapy, with its potential effect on future generations, remains the subject of intense ethical and philosophical discussion. In 1990, researchers at the US National Institutes of Health conducted the first approved human gene therapy trial. It involved the transfer of the gene encoding adenosine deaminase into two patients with severe combined immunodeficiency. Ashanti DeSilva, aged four, experienced a partial correction of her condition. By the end of that decade, the gene therapy field was riding the crests and troughs of the new

wave of medical research. The number of clinical trials for gene therapy approved worldwide had climbed rapidly, from two in 1990 to 116 in 1999, but in the latter year the first major adverse event was reported. Jesse Gelsinger, 18, who had a relatively mild form of ornithine transcarbamylase deficiency, died due to vector-associated toxicity. Hopes rose again in 2000 with what was hailed as a genetherapy grand slam. French researchers corrected a rare form of X-linked severe combined immunodeficiency (SCID-X1) in 10 children with the transfer of bone marrow cells genetically modified by a retrovirus vector encoding human c. In collaboration with the French team, Australian researchers treated a nine-month-old boy with SCID-X1 at the Childrens Hospital, Westmead, NSW, in 2002. They achieved only a partial immunological reconstitution.6 However, also in 2002, two of the French children developed a leukaemia-like condition. The trial was restarted using lower doses of modified cells, but a third child developed a similar condition in 2005. Two of the children responded to chemotherapy but the third died. Professor Ian Alexander, the head of the Gene Therapy Research Unit, an initiative of the Childrens Medical Research Institute and the Childrens Hospital at Westmead, says such adverse events have led to a degree of scrutiny not experienced by other therapies. They have also bred too much caution about gene therapies in regulatory bodies and researchers, he says. The bottom line is that the clinical trial activity is what is going to take us forward, he says. You could get concerned about a theoretical risk, but for many of these patients the disease that they suffer poses a far greater one. And with risk an inescapable part of clinical research, balancing it against benefit is the key to moving forward, Professor Alexander says. Regulatory authorities have a responsibility to protect public safety, scientists and clinicians are trying to drive new therapies forward, and theres always got to be a balance struck. The development of efficient and safe gene transfer remains the key focus of the move from animal models to humans. Professor Alexander, whose team undertook the SCID-XI

trial in 2002, will be part of the follow-up multinational phase I/II study, which will use a different gene transfer technology and is set to begin by the end of this year. There is so much exciting stuff on the horizon, he says. What we are going to see in five years are very clear, unequivocal successes. Dr Jude Samulski, the president of the American Society of Gene and Cell Therapy, says single-gene defects are where the quickest successes will happen.

If you have a single-gene defect, then if you replace it, chances are you fixed it. If you go after the complex disorders, like cancer, where multiple things can contribute to the disease, its really, really tough to say what is the best approach, he says. The single-gene defects are clearly going to be the playing field where this technology will get perfected and move forwards. And as the field moves onto the front foot, it will hopefully take with it the lessons learnt

from its time in the corner, says Dr Samulski. I think our community failed completely to put in perspective what happens in our world and what happens daily in the other [research] communities, he says. Look at any study on small molecules for chemotherapy and there are hundreds and hundreds of failures that result in death. Striking the balance between hype and hope has been another lesson, Dr Samulski says. If you oversell something,

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