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Recent Publications dealing with Duchenne Muscular Dystrophy.

  • September 10th 2008
  • Posted by Karl Bettleheim at 20:31pm
Although there have been some very good studies published recently especially on the use of viruses to transfer human genes, the three articles, which were published in ‘Nature’ (1,2,3) a few weeks ago caught my eye and I felt they needed to be brought to the attention of the DMD community. This review therefore again takes on a slightly different form but I nevertheless hope it will be of interest.

While ‘Nature’ publishes articles by scientists in all fields of scientific endeavour from Cosmology to Microbiology, it often also includes review articles dealing with matters of more general interest. The three articles I wish to discuss fall into this line. They were published as a group in the order in which I shall now discuss them.
The first article by Butler (1) is entitled ‘Crossing the valley of Death’. In the subheading of his review, Butler claims that a chasm has opened up between biomedical researchers and the patients who need their discoveries and he specifically addresses the question of how the ground shifted and whether the US National Institutes of Health (NIH) can bridge the gap which has opened. He points out that the mission of this organisation, which was established 50 years ago was then and remains today to pursue fundamental knowledge and apply it “to reduce the burdens of illness and disability”. The basic research, which the NIH has funded and pursued, has undoubtedly been of the highest standard and there is no question about that. He quotes A. Schaechter, the head of molecular biology and genetics at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, USA, who pointed out that “We are not seeing the breakthrough therapies that people can rightly expect”.
Medical scientists doing fundamental research appear to have diverged from the pharmaceutical industry over the last two to three decades, such that the carriage of these discoveries from the scientists which the pharmaceutical industry was supposed to do, is now hard pressed to be able to do. The abyss, which has been left between these two groups, has thus been labelled the ‘Valley of Death’. It seems that the basic researchers, breaking new ground, and the clinicians, looking after their patients, do not communicate.
The NIH is trying to bridge this gap by setting up a consortium of 60 Clinical and Translational Science Centers (CTSCs) at many research institutes, universities et cetera, across the US. When they are set up (by 2012) they will share an annual budget of US$500 million. So far the consortium has reached 38 centres since it was launched in 2006. Although this budget looks large, it is less than 2% of the NIH’s annual budget of $29.5 billion. Also, at the moment everyone involved with this translational research seems to have a different idea of what it actually means. Butler points out that a lot of translational research is just re-branding, being clinical R&D (Research & Development) by a different name. The hope is that this barrier in the transformation of basic-science breakthroughs into clinical applications (‘bench to bedside’) will be broken down and thus enable more research on human subjects and samples to be performed so that hypotheses that are more relevant to people than to animal models are generated. From our point of view this means that they should move away from treating mice to considering humans instead!
While half a century ago most medical research was predominantly done by physician–scientists who also treated patients, this changed with the advent of molecular biology and most biomedical research is now done by specialist scientists. The clinicians who treat patients find the research increasingly complex and are unable to keep up with the discoveries. In addition, the pharmaceutical industry, while spending more on research is delivering fewer products. He quotes Garrett Fitzgerald, head of the CTSC based at the University of Pennsylvania in Philadelphia, who says: “There is a real crisis in the industry”.
The term ‘translational research’ first appeared in PubMed (the internet database of medical publications) in 1993 and by around 2000, following a discussion on this, two blockages were pinpointed. The first blockage that was identified was the prevention of laboratory advances being converted into new medical products and tests in humans being performed. The second blockage was stopping proven improvements in treatment, e.g. a new drug combination becoming adopted in medical practice.
He points out, (and as an ex-scientist, I have to agree) that most basic scientists have few incentives to move out of their area of expertise and get involved with the complex legal, regulatory and patent issues. Scientists making a breakthrough in their research have this breakthrough being taken over by their employer who justifiably states that as the scientist was paid to do this work and it was done on the employer’s premises and using the employer’s facilities, the discovery therefore is clearly the employer’s property. The scientist may get a small remuneration at the discretion of the employer. That is also why some scientists leave their employer and form their own companies but here again they have other great problems and huge expense in getting their product to the clinicians. Many such companies have collapsed and many will collapse in the future too.
While the basic research discovery can (and usually is) published in an appropriate prestigious scientific journal which looks very good on the scientist’s curriculum vitae, the translation of the discovery into a usable product does not carry this kudos, is therefore rarely published or even publishable and does nothing for the scientist’s curriculum vitae. When Elias Zerhouni became director of the NIH in 2002, he said: “There was a widening gap between basic and clinical research, which if left alone would have been a major barrier to progress.” As head of the world’s top-spending biomedical research agency, he was therefore under pressure to make progress. With the NIH’s budget having doubled since 1998 to $27 billion in 2003, taxpayers were demanding a return on their investment. He continued: “That is the accountability factor that Congress is asking us to address”. Following a series of meetings between scientists and clinicians he realised that it was a priority: “to get over this gap” by redesigning the agency’s translational research programmes.
There had been 78 General Clinical Research Centres (GCRCs) created in 1959 at universities and medical centres nation-wide. These had carried out clinical trials but in order to tackle the new issues these GCRCs will be replaced by CTSCs. Instead of being run by a clinician-scientist as in the old days, they take the form of larger, multidisciplinary groups, including not only basic scientists and clinicians, but also bio-informaticians, statisticians, engineers and industry experts. These groups, he hopes, will stand on that bridge that crosses the ‘Valley of Death’.
These developments are watched with interest in other countries, including Britain, which is second only to the United States in biomedical research output. The UK government last year announced a doubling of the Medical Research Council’s budget to almost £700 million (US$1.3 billion) by 2010, largely to finance a new focus on translational research. Similar actions are proposed in a number of European countries. A multimillion-euro network of biomedical translation hubs across Europe, based on existing research centres is planned. It is now only a matter of time before we see results. Some critics argue that, while only a tiny fraction of the NIH budget, and much of that is just reshuffled from existing clinical programmes, the CTSCs are little more than business as usual.
In the current system, where most of the research grant applications are driven by scientific investigators, the system rewards individual success but does not do very much to encourage the type of collaboration demanded by translational research. Alternative models for doing translational research exist, like the Multiple Myeloma Research Foundation, based in Norwalk, Connecticut, USA, and other charitable groups that operate more like businesses in their drive to get research into the clinical trials. We should strongly push for this method in my opinion. With these ideas in mind, Zerhouni realises that there is a need to reform the NIH and he hopes the CTSCs will have the freedom to explore a diversity of approaches, however the author of the article concludes that it will still take many attempts to cross the chasm.
The theme of the second article (2) is a discussion by the author of various aspects of clinical trials. She opens with a description of a meeting of the American Association for Cancer Research in San Diego, California, which was held in April this year (2008). Nobel laureate Sydney Brenner, whose pioneering work had been on a simple flatworm, brought the crowd to its feet by championing experiments on a more complicated creature: Homo sapiens. He said: “We don’t have to look for model organisms anymore because we are the model organism”.
Instead of translational research in which laboratory data are transferred to the patient’s bedside, he advocates going the other way. During clinical trials the observation of patients’ unexpected responses are valuable human experiments, and failed trials can stimulate new hypotheses that may help refine the experiment in its next iteration. The author then proceeds to give three examples of this type of procedure.
The first example, she discusses, concerns the strange results from an experimental cancer drug called gefitinib. This was one of the first generation of so-called ‘smart drugs’, which were designed to target a specific protein, in this case one called epidermal growth factor (EGFR). This is produced by a number of tumours at higher than normal levels and thus stimulates the growth of the tumour in a type of vicious downward spiral. Gefitib, which had been marketed by AstraZeneca as Iressa, was used to treat a severe lung cancer called non-small-cell carcinoma. While spectacular results were obtained with some patients, the results being described as ‘magical’ by one clinician, the overall general response rate was not significant. Therefore the drug was withdrawn. Subsequently it was found that the patients of most of the tumours that responded to gefitinib had a mutation in the EGFR gene, that made the EGFR more sensitive to gefitinib. Several clinical trials are now under way to determine whether the drug is effective when it is given only to the patients with a mutated EGFR receptor. Another problem was also noted that some patients, who had initially responded to gefitinib, later failed to so; it has since been found that a secondary mutation occurred in these patients rendering the EGFR insensitive to gefitinib. Other mutations were also shown to occur occasionally, which permitted the tumour cells to grow even when EGFR was not working. Soon a second problem was observed. Some patients who did initially respond to the EGFR inhibitor subsequently become resistant and genetic analysis of their tumour samples and cancer cell lines revealed that these resistant tumours had acquired secondary mutations that rendered the drug ineffective. Current studies are under way to determine, whether these secondary mutations can be overcome, perhaps with another drug. One of the problems with these studies was the difficulty of obtaining tissue samples because separate ethic committee approvals had to be obtained in many instances.
The second example deals with the gene therapy treatment of X-linked severe combined immunodeficiency (X-SCID). She notes that since 2002, 5 of the 21 children who had received a high-profile, experimental gene-therapy treatment for X-SCID have developed leukaemia. Initially the two X-SCID trials, in France and Britain were seen as being successful. The treatment used a virus to put a functioning copy of the mutated gene into the patient’s bone marrow stem cells, which generate the immune cells. The virus was expected to integrate randomly into the patient’s genome i.e. attach to any random area of the patient’s genetic make-up, but it was found that the virus preferentially inserted itself next to a cancer-causing gene which caused leukaemia in mouse models. When in 2005 the third case of leukaemia was seen the trial was put on hold and everyone worried about the future of gene therapy.
As gene therapy is probably such an important tool, scientists probed this problem and using a very specific molecular technique, were able to locate where the viral genes were integrated and it was noted that they slotted into hundreds of different sites, preferring to settle near highly expressed genes. It was believed that viral elements, designed to stimulate the production of the missing gene products, also stimulated some other genes, which then led to leukaemia. A new development of the viral vector that includes genetic control regions making it unlikely to activate nearby genes will be used in the next trials for X-SCID. In addition, four of the five children, who developed leukaemia were successfully treated and their repaired immune systems remained intact. In no way could the development of leukaemia have been foreseen and the repair achieved if the trial had not been carried out on the patients.
In the third example, the author discusses a new approach that had been developed to treat Human Immunodeficiency Virus (HIV) infections. While many attempts to develop a vaccine have failed, Merck’s approach was to stimulate a T-cell response, rather than to form antibodies. Due to the raging HIV epidemic, the decision to move this promising candidate into clinical testing went ahead rapidly. However, the unexpected happened, the vaccine made some study participants more susceptible to infection. The scientific community was at a loss to explain this and the trial was stopped. Currently a number of hypotheses have been put forward and some 25 research proposals to investigate this failure are in the pipeline. Again this study needed the use of human patients for the investigation.
In her concluding remarks, the author comments that it is the HIV community which has a level of organisation and persistence which is rare in other conditions, where most lessons are being learnt. I would suggest that if the DMD community were to attempt a similar level of organisation and persistence to the HIV community, we would be well on the way to a cure.
The third and last paper of this set (3) deals with the Ludwig Institutes of Cancer Research, of which there are nine scattered around seven countries. Following an amusing account of their inception in 1984 when the American billionaire Daniel Ludwig offered researcher Webster Cavenee US$3 million a year for a new cancer research institute, this concept has grown to its present level of excellence. Cavenee’s centre in the Ludwig Institute for Cancer Research (LICR) in San Diego, California, USA currently has an annual outlay of $100-million and spends 15-20% on an infrastructure that deals comprehensively with intellectual-property issues and clinical-trials management. Larger sums are spent on the facilities that make some of the biological reagents, which are required for these trials. As a personal note the Melbourne (Australia) branch of LICR is next door to the Department of Microbiology and Immunology where I worked for many years. I heard just before I left that they were going to take over the building in which I had been and we would have to move to another. This shows how successful they are.
In the 20 years as scientific director of LICR, Lloyd Old prefers to use the term ‘Clinical Discovery’ rather than ‘translational research’ for the goal that he has pursued throughout his directorship. His aim has been to get the cutting-edge as close to the clinic as possible before passing it on to the drug companies. There has been some criticism of the opaque nature of some of LICR’s decisions and that they should be more open to scrutiny. This may still reflect Ludwig’s publicity-shyness, and the way he had carried on his business interests.
The key to the success of LICR has been Old’s mantra about control in translational research. By ‘control’ he means that LICR retain the intellectual–property rights and maintain a support staff that permits the researchers to participate at least to some extent in the early-phase clinical trials rather than giving it all to the drug companies. Thus the LICR has become one of the largest not-for-profit DNA patent holders in US biomedicine. The author then quotes statements from a number of senior researchers, which can be summarised by the words of one: “That gives us immense power to get the job done”.
While they certainly do not want to cut out the pharmaceutical companies, they want to be in the situation of being ‘in pole position for transition to the clinic’. LICR’s control also ensures that their researchers have access to the reagents needed for their trials and have dedicated centres for the production and storage of specific reagents which in some instances can cost millions of dollars. I hope I may again add a personal note: in my work I had made my own specific reagents which only had very limited use by a small number of reference laboratories around the world; if I had depended on a commercial company for the reagents they would have cost a vast sum of money and I might not have been able to rely on a continuous supply because of the production company’s other interests.
The author quotes the chairman of the German Cancer Research Centre, Heidelberg, Germany who works with the LICR: “the LICR is really unique in providing such an incredible infrastructure,” he goes on: “I don’t know any other academic institution that does it on this scale.” There follows an extensive discussion on the development by the LICR of cancer vaccines, one of which is about to undergo phase III clinical trials with a pharmaceutical company, a spokesperson for which stated: “we would have struggled to find the resource and commitment to do that [initial study] alone.”
The author then describes a visit to LICR’s plush New York office where she relates that there are 10 metres of shelving devoted to the regulatory paperwork required to test 11 new agents in humans which are currently under investigation i.e. just under one metre of paperwork per agent. Fifteen employees deal just with this apparently uninteresting, frustrating and potentially overwhelming task of translational research. The LCIR’s endowment of US$1.4 billion is not in the same league as some others but it is nevertheless substantial. By concentrating on one area, namely cancer, it is able to fulfil its role admirably.
There have been mistakes made in the past and there has been criticism about its lack of openness but as the author states in her final section: “results matter” and she quotes a leading member: “judge us by our results, not by the way we’re doing it.” and who can argue with that? To date the LICR has only one licensed therapeutic success to point to — granulocyte-macrophage colony-stimulating factor (GMCSF). This is used to stimulate production of white blood cells after chemotherapy.
“This is not a field with quick wins” is the point made by the author when comparing this with other cancer treatments which have recently been developed. A programme started by another group in 1998 has so far cost $100 million and even now has only recruited 32 out of 121 candidates for its clinical trial. So LICR’s 120-odd clinical trials since 1996 should be considered as being on good course. With this rate the future of the LICR and of the development of cancer treatments looks very hopeful.
Personal Concluding Remarks
I have spent a lot of time reading and abstracting these papers but I think it is time well spent because it explains the pitfalls and problems of getting a reagent that acts so wonderfully in, say, mice to our patients with DMD. I hope the review of these papers should at least clarify the problems. I think we should try to move forward as fast as possible to deal with the chasm between the wonderful scientific results which are continuously being published on various aspects of gene therapy, exon-skipping, utrophin up-regulation, reading past stop codons etc. We do not have the leisure time to wait for up to a metre of paperwork on trials to be completed. The most important part of these reviews is the realisation that we humans are unique as are all animal species and therefore just because something works well in mice does not mean it will necessarily work in humans or even the reverse. As an example, the guinea pig, an animal whose name is synonymous with testing, has an extreme sensitivity to most antibiotics, including penicillin, which kill off the intestinal flora and quickly bring on episodes of diarrhoea and in some cases, death. Perhaps we need to take more risks and let the scientists work more closely with the patients who do not have the time to wait - especially the older ones.
The ideal solution might be to find a Mr. Ludwig who would be prepared to invest money in founding an institute in the study of inherited diseases like DMD and X-SCID, in which we would have a significant control. Until such a miracle turns up we should become even more proactive with the government bodies who control clinical trials to try to remove some of the centimetres of shelved paperwork that has to filled out before an experimental drug can be tried on humans. We must also insist that all scientific endeavours funded by us must be prepared to follow through to patients’ bedsides or we are simply wasting our money given that our goal is to treat and cure and not simply to advance scientific knowledge.
Since writing most of this review, a report from the New York Times Business section dated 17.July.2008 has come to my attention. This report deals with a lawsuit, which had been filed by a mother of a 16-year-old son, Jacob, with DMD, suing for access to the drug PTC124 for her son. According to the lawsuit. “Without it, Jacob will not survive.” The mother “with a master’s degree in nursing, was instrumental in getting federal legislation passed to provide more research money for the disease, despite the challenges of working from her family’s farm in rural Minnesota”. The response by the company has been summarised in the report thus: “The burden is on everyone to ensure that safety is kept in mind in each step and that we don’t get ahead of ourselves in our enthusiasm,” said Dr. Richard S. Finkel, a prominent expert in Duchenne at the Children’s Hospital of Philadelphia, which is working closely with PTC Therapeutics on its PTC124 research”. This report clearly reminds us of the importance of being proactive especially in the research, which we support with our hard-earned money. We do not have the luxury of being able to wait. We need to demand that our children get the benefit of the research, we fund, not only someone else’s grandchildren or even great grandchildren!

References.
1. Butler, D. (2008) Crossing the valley of Death. Nature. 453(7197):840-842.
2. Ledford, H. (2008) The full cycle. Nature. 453(7197):843-845.
3. Pearson, H. (2008) A case history. Nature. 453(7197):846-849.
Karl A. Bettelheim


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