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Scripps Salomon on Microarrays for Studying Kidney Transplant Rejection

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At A Glance

Name: Daniel Salomon

Background: 1993-Present — Associate Professor, Department of Molecular and Experimental Medicine, the Scripps Research Institute, San Diego. Director of the Center for Organ and Cell Transplantation, Scripps Green Hospital; 1999-2003 — Chair, Biological Response Modifiers Advisory Committee of the US FDA; 1990-1993 — Laboratory of Immunology, NIH; 1985-1990 — Director and Founder of the Heart Transplant Program at the University of Florida.

Education: BS, Chemistry, Northwestern University; MD, Stritch-Loyola School of Medicine

A research team led by Daniel Salomon, associate professor in the department of molecular and experimental medicine at the Scripps Research Institute, was recently awarded a $12 million NIH grant to study kidney transplantation using genomic technologies. Over the course of five years, Salomon and his colleagues intend to monitor gene expression and other genetic traits of several hundred patients who have undergone kidney transplant surgeries. This past week Salomon, who formerly served as co-director of the microarray core facility at Scripps, answered questions from BioArray News about the project and the use of microarray technologies in attempting to uncover why some patients reject transplanted kidneys and others do not.

How did you get involved in using microarray technology?

I’m a physician-scientist, so I have very strong clinical interest in organ transplantation and cell transplantation. I also see patients and am the director of our transplant program. At the same time, I spend the majority of my time in a basic research lab, where I’m doing research on a number of different things, all related to organ and cell transplantation. So, my interest in gene expression arrays developed out of a growing awareness that this technology, as part of a bigger project of systems biology, was extremely appropriate now for applications in transplantation.

Is the use of microarrays now normal practice within transplant research, and do you foresee greater use of the technology in this field?

I would say it’s far from a general practice at this point, and I think now one has to stop and think whether we’re talking research or actual clinical applications. What’s easy to say is that at present there are no clinical applications of this technology in transplantation. With that said, it’s my express purpose in life right now to validate the use of this technology for clinical use. In that regard, just at the end of last year, I got NIH funding of over $12 million to do a program project in just this — looking at gene expression profiling, tandem mass spec proteomics, and a number of different strategies for genetics using single nucleotide polymorphisms to correlate with clinical events in kidney transplant patients.

Can you tell us more about the program and its goals?

The premise is that gene expression profiles, tandem mass spec profiles, and the genetics of the kidney donor and recipient are all opportunities for which this technology is ideally suited. You have to think of these things in two major areas. Area number one is the idea of establishing profiles that become diagnostic. In the process of profiling one doesn’t necessarily need to understand the specific molecular biology or pathway, but one has to have confidence at the level of clinical application in the value of the profile itself. So, the first of two major goals of the project is to test the hypothesis that these sorts of profiles will match with high confidence as a diagnostic states such as acute rejection, chronic rejection, which we often refer to as chronic allograft nephropathy, and patients that never have a rejection and have fantastic kidney transplant function. That’s what this is all about. If you could demonstrate that, then its clinical utility becomes a reality.

Could you predict acute rejection? Could you determine if the amount of immunosuppression you’re giving a patient at any given time post-transplant was adequate? If you could, then you could say, ‘Oh, my patient’s transplant immunosuppression is either adequate or I’m giving too much, let me give a little less.’ That’s a good thing because these drugs are toxic. Then you give a little less and you go back and profile and say, ‘Hey, it still looks good, let’s give a little less.’ And at a certain point, you’ll fall below the threshold for that patient. Truly personalized medicine for a transplant patient. There’s always going to be a down side to immunosuppression as long as we’re using the current generation of drugs. In the meantime, [we could] use these technologies to optimize the therapies of patients so you get the maximum benefit and you take what’s left in the trade-off. That’s incredible. That would change the way we practice medicine in transplantation.

How far away are we realistically to being able to apply this technology in clinical practice?

I’ve thought a lot about this, because that’s the key question that everybody has asked me. I cannot at this point justify managing a human being’s immunosuppression until I’ve really validated this technology. Our data is good — I’m not having a crisis of confidence. But I have a five-year grant here to really do it right. And to me, the responsibility to my patients is much higher. My plan in the next three years is to validate [the technology] for myself, so I have full confidence that this can be used diagnostically. And if it can at the end of that three-year period, then I want to launch a prospective trial to test that. So, I’m thinking that within five years we can move this to the verge of clinical application.

Now, I said there were two things in this project. One is this diagnostic profiling. The second is really gene discovery and understanding the science of transplant biology, and that’s a big job. That’s going to take years to do. What we’re going to do is create this remarkable database that will move our understanding of transplant biology forward significantly and open up lots of follow-up studies that need to be done to really understand what’s going on.

Will the database be shared with the broader research community?

Most definitely, as it evolves. At the moment, we’re building clinical databases, where everybody’s got 10 clinical centers around the United States putting in their institutional review board applications, so we can start collecting samples. Nothing has happened yet in the form of data generation. On a yearly basis, the data will be published and made available to the community by the web. By the time the project’s over, every piece of data will be available to other scientists around the world to use.

What kind of arrays do you use?

There are a couple different technologies here. The first are the commercial U133 Plus 2.0 Affymetrix Human arrays. We are also using [Affymetrix’s] 100K mapping arrays. We are also going to be testing sometime later this year the 500K SNP mapping array [from Affy] as well. We are also going to be doing a large number of custom-designed resequencing arrays, which is yet another Affymetrix technology. The plan there is we’re going to test, using the resequencing arrays, 250 genes that we will pull out of our data over the next three years from both proteomics and gene expression profiling that we feel are the cream, and use them to look for SNP changes in those specific genes.

You had two articles published in the American Journal of Transplantation last year. Can you tell us about those?

Those were the projects that were published and that was the data upon which the program project was essentially based, at least the gene expression profiling part. There’s also unpublished data on proteomics and genetics. So, the first one makes the point for the first time that one can use peripheral blood lymphocytes to profile acute rejection with certainty in patients, and also showed you could do it with the biopsies as well. But the idea that you could do it with peripheral blood is just amazing. If that can be validated, that would be for the first time a situation in which one could prevent having to put a big needle in somebody to make a diagnosis of acute rejection. So, we’re very excited about that.

It, of course, was the proof of principle for what I think is a much more major thing, and that is the ability to screen for the adequacy of immunosuppression. The point of the exercise was to demonstrate that peripheral blood lymphocytes, that their gene expression profiles, actually reflected what was going on in the kidney transplant. There’s been 30 years of effort trying to find peripheral blood correlations that did this and that have generally failed. Once one could demonstrate that ... then you could do the adequacy of immunosuppression testing.

Has your work drawn any commercial interest from pharma or diagnostic firms?

Yes. We are in discussion at a very serious level with two large pharmas that have major stakes in clinical transplantation for work in both kidney transplantation and liver transplantation, which we’re extremely interested in as well.

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