Title: Integration and translation: driving stem cell therapies toward the clinic Author(s): Alan Trounson Source: Regenerative Medicine. 3.3 (May 2008): p269. Document Type: Article DOI: http://dx.doi.org.ezproxy.lib.monash.edu.au/10.2217/17460751.3.3.269 Copyright : COPYRIGHT 2008 Future Medicine Ltd. http://www.futuremedicine.com/loi/rme Full Text: Author(s): Alan Trounson 1 How did you initially become involved in stem cell research? In the late 1970s in Melbourne, we were working with embryo transfer and in vitro fertilization, publishing much of the early work that is now the standard technology worldwide. In the mid-1990s, I became interested in how cells differentiate further, because we could only keep the cells for 6-7 days in the laboratory but that did not tell us anything about how the cells were differentiating into the various cell types (heart, muscle, nerve cells and so on). I was interested in those early stages of development and I thought that it would be very interesting if we could derive embryonic stem cells (ESCs) from humans as they had in the mouse. I wanted to study how cells change from being undifferentiated to the final differentiated product and hoped that this might lead to better understanding of some developmental abnormalities and childhood cancers: that was the initial driver. I started that work with Dr Ariff Bongso in Singapore. Dr Bongzo had spent a sabbatical leave with me previously and I decided to spend a sabbatical leave with him in Singapore in 1995-1996. During those early studies we were establishing human ESC cultures. In December 2007 you took over the position of President of the CIRM. What attracted you to this role? I have had a very satisfying career in research. I had a research center with over 120 people working with me in Melbourne, and last year I was awarded four major grants and had papers published in Science and Nature , so I felt really satisfied with the type of work I had been able to do in my own research. When I was approached for the CIRM President position I was initially surprised but then I thought, wouldn't it be exciting to facilitate the movement of stem cell research into the clinic? That is the mission of CIRM: to take all of these early discoveries and translate them into clinical medicine. I struggled with the matter of finishing a laboratory career and becoming more of an administrator, but this is one of those spectacular opportunities that come once in a lifetime and to make another really major contribution towards the end of my career. For me it was one of the best jobs going in the world. What do you feel are the main goals for the CIRM over the next year and, longer term, over the next 10 years? Over the next year I am keen on integrating the pipeline: taking the major discoveries that are happening at the present time, all over the world but particularly here in California, and moving them into a developmental pipeline to be translated to clinical medicine. Much of the work is extremely basic, in laboratory Petri dishes, and there is a need to determine how to scale-up manufacturing; look at the stability of the cells during extended culture and begin translation into the pipeline ready for clinical application. We need to link what is going on currently, where adult cells are actually already being used in clinical trials, with the earlier, more developmentally capable cells, such as ESCs. The mission of CIRM is to start delivering clinical treatments over the next 10 years and we are slated to have at least one or two clinical trials underway within that timeline. I think we will easily achieve that (probably more than that) most likely using pluripotent ESCs. I think we will be carrying out clinical trials involving pluripotent, adult cells and drugs in a complimentary strategy. These strategies might also require
some suppression of the immune system, some repair of, for example, autoimmunity and some repair of the damaged tissues. Importantly, this will require developing new drugs or using existing drugs in new ways, to accommodate the regenerative capacity of stem cells. The first well recognized trial is likely to be in spinal injuries. In addition, retinal repair, repair of lung tissue and cardiac repair after myocardial infarction are all areas likely to move into clinical trials within 10 years. What are the main barriers to translating stem cell therapies to the clinic & how does the CIRM aim to overcome these? A lot of the barriers are set very high by the regulatory authorities, perhaps appropriately. While these cells have an incredible potential, in their native state they are known to form teratomas and we would not want those spontaneously developing in patients. So the bar will naturally be set quite high for these pluriopotent cell types, and this will mean that the regulatory processes are going to be very demanding, in terms of the supportive data required on safety and efficacy in preclinical models. With this in mind, it is clear that cost is another important issue: the first clinical trials are likely to cost many millions of dollars for safety and efficacy. In the area of drug development, a very large amount of money must be spent to get new drugs into medicine and it is not unlike that for the cell therapies. We do not have big pharma engaged in any sort of cell therapy, so we are either going to have to forge relationships with major agencies, such as the NIH or to help investment capital to move in and support the biotechnology companies to undertake the initial clinical trials. I hope we will be able to persuade the pharmaceutical industry that cell therapy is in their interest and to become partners in the process. It is a matter of timing, rather than whether it will or won't happen. The timing for the pharmaceutical industry needs to be appropriate and hopefully we're moving closer to the time where they feel an engagement is in their interests. If we can do that, I think we have got all of the capacity to develop the therapies and apply them to the large populations who are desperately in need of them. Why do you think pharmaceutical companies have failed to get involved in cell therapies? I think it has been hard for them to understand the product and see where the profit margins are. Because it is so expensive to develop these therapies, you need to know how you are going to recover that investment in terms of products. That has not been easy but I think they are starting to see ways, particularly when there are combinational cell and drug treatments proposed. I think there has also been reticence because the US president and federal administration have not been supportive: the companies have been sensitive to the ethical debates over ESCs and have not wanted to engage too deeply. However, all of these situations are coming to an end in importance, as the public becomes more and more supportive of finding out whether these cells can convert their potential into real promise for patients. The CIRM recently launched the Disease Team Planning Awards & New Cell Lines Awards. Could you outline the scope & importance of these grants? At this stage we are trying to help people get organized on the disease teams so we have given relatively small grants for them to negotiate with one another to form appropriate relationships. This is to enable the pipelines to begin functioning with an end point of an an Investigational New Drug Application to the US FDA or other appropriate regulatory authorities for human studies. Later in the year there will be a call for the teams to apply for disease grants and we will then select the best-formatted teams. That could be one organization or may well involve a large number of organizations, including universities, biotechnology companies and drug companies. In the new cell line program, we are looking at different ways to develop pluriopotent cell types and bringing in the new area of induced pluripotentiality (induced pluripotent stem cells [iPSCs]), in which skin cells, for example, are converted to cells with properties similar to ESCs. We are interested in that area because it may well flourish and we want to see our scientists be part of this. There are also other ways of looking at developing stem cells from activated eggs: the nuclear transfer/therapeutic cloning work is also
still something we are interested in. We have letters of interest from a number of organizations and the quality of the applications will be assessed by independent review. Another major program of the CIRM is the Major Facilities Grant Program. CIRM is contributing US$262 million to the development of up to 12 really exciting stem cell institutes. With the institutes contributing twice as much again, we are looking at approximately US$700 million of new stem cell research facilities developing in California. The details will not be finally decided by the ICOC until the first week of May but it is very clear that we will be helping most, if not all, of those applicant institutes to build new facilities. It's a fantastic initiative for California and will draw a large number of scientists to the area. With the recent developments in iPSC technology, are embryonic stem cells becoming irrelevant? How will the development of iPSCs affect the future strategy of the CIRM? I do not think ESCs will become irrelevant, I believe they are well and truly on the track to the clinic. It is still a little early to determine whether iPSCs truly behave in the same way as ESCs. Also, as the scientists working with iPSCs point out themselves, these cells are not much use for clinical application at this stage because cells containing genes in unidentified positions in the genome would not be acceptable by any regulatory authorities. It would be very unwise to hinder in any way the progress of ESCs, which are about to go into clinical trials, in favor of another cell type that is yet to be fully understood and needs a whole new phase of alteration to make them clinically useful. The CIRM has opened these awards to private biotechnology companies. What do you feel are the benefits & problems of state funding to private companies? What strings will be attached to grants awarded to for-profit recipients? Thus far we have not funded any companies but the time is approaching now, as companies have joined in partnerships with other institutions to apply for grants. It is about trying to include the for-profit sector and still protect the interests of California citizens who have invested in it. There is always the concern that public money could be provided to private companies for the advantage of shareholders and that is really not how public money should be spent. On the other hand, we cannot actually get these treatments into the clinic unless we engage with the private sector because they have the skills we need in understanding what is required in translation, how to meet the regulatory requirements and how to source sufficient collateral money to do the studies. We do not really have a choice. What we need to do is assist companies to initial clinical trials and begin the evaluation process. We must also try to make sure that the cost of those treatments is contained. That will be one of the CIRM's roles, to ensure that the costs don't escalate way out of the affordable range of ordinary people. We need to negotiate agreements with the companies so that they will not escalate their recovering costs and I think we will. I do not think that the companies want to make the treatments inaccessible so I think we can work together as partners in the process. The public of California, having agreed to the establishment of CIRM, trusts that CIRM will look after their interests when it comes to clinical applications. The intellectual property issues are still being negotiated but if a company receives a grant they have to conform to regulations that state that intellectual property is a sharing process. There is a proposal for some sort of loan system. The model has not been finally determined as yet but it is an interesting idea. Many of the companies would prefer a loan, as opposed to a grant that might occupy some of their intellectual property rights. Some grants, for example for clinical trials, will not involve intellectual property. A loan agreement may avoid handicapping a company because otherwise CIRM may occupy a significant amount of their intellectual property. If a company receives a grant from CIRM to develop a product that goes on to become profitable, some of those profits would return to the CIRM and so to the state of California. The agreement at the moment is for 25% of profits to be returned.
Are you expecting changes in the laws governing federal funding of stem cell research after the forthcoming US presidential elections? How is that likely to affect the CIRM? I definitely expect changes. Clearly, the democrats have a very different view to President Bush; I believe both Senator Clinton and Senator Obama are very supportive of stem cell research, as was President Clinton. In the case of the Republicans, it is clear that Senator McCain has a different view from President Bush so we will certainly see some liberalization. But I would be doubtful whether it would be the full liberalization that is envisaged by the Democrats: there are some very conservative elements in the Republican party. Whoever wins the election, I am certain there will be a change and that change will be very much in the interests of the patients and researchers. Eventually it will be very much a boost for the area. For CIRM, it will result in the ability to engage with the NIH in codeveloping the stem cell area. We do not want to be competitive to the national interests, we want to be working in association with them. If there was some liberalization towards stem cell research it would enable us to find ways to work together to enhance the area. I think that is a matter for future negotiation. But it would be incredibly rewarding if the NIH are able to increase their traction in this area. They certainly are contributing even now, but they are handicapped with what cell types researchers can work with, which prevents some of the work flourishing. If these restrictions are lifted and we agree to some joint developments, where appropriate, that will accelerate the whole area very significantly and patients could look forward to more clinical trials more quickly. Advances have been made recently in cloning ESCs, both in human & primate cells. Is therapeutic cloning a strategy that you think will be important for future research? The big problem in the area is the very large number of eggs necessary. If you're talking about human eggs and you need 100 or 200 eggs in order to make a hESC line it is a difficult proposition because you need a lot of women prepared to donate eggs. Egg recovery is very demanding: it is one thing if you are trying to establish a family but quite another to become a donor, especially since it is not permitted to compensate these women for undergoing treatment to donate eggs. With the large numbers of eggs required, the difficulty escalates substantially. However, if the efficiency changed, if we could make ESC lines with, for example, ten eggs, it would change things dramatically. The opportunity to make cells by this method is extremely attractive but the practicalities make it extraordinarily difficult. Author Affiliation(s): 1
CIRM, 210 King Street, 3rd Floor, San Francisco, CA 94107, USA.
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Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Alan Trounson Source Citation (MLA 7th Edition) Trounson, Alan. "Integration and translation: driving stem cell therapies toward the clinic." Regenerative Medicine May 2008: 269+. Academic OneFile. Web. 19 Feb. 2014.
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