Research Update:
Tony Futerman Ph.D.

It is with great pleasure that I am writing this brief article to update readers on research progress in my laboratory over the past couple of years, and to thank all the generous donors who have made the work possible. I can truly say that without the remarkable efforts of the CGRF, my research would not have been possible.

First a little background.

I have had the honor of being supported by three research grants from the CGRF over the past decade or so. Each time that I have submitted an application for a renewal of my funding, my knees have trembled! Would I receive an additional award? Do my scientific peers, who independently evaluate my research grant applications, think that progress has been sufficient to merit another award? What would happen to the research on neuronopathic Gaucher disease in my laboratory if the work was not funded? Fortunately, I have been privileged to receive funding, with the most recent round of funding being awarded towards the end of 2010, for a period of three years. And for this I express my thanks, not only to my scientific colleagues who rated my research as worthy of funding, but also to the CGRF and its generous and committed donors.

How much money is needed for research?

Some of you may be wondering why so much money is needed for scientific research (for your information, the grant which I was just awarded is worth $100,000 per year for three years). Well, research is very expensive. A major expense, and perhaps the major expense, is personnel. I currently have two outstanding graduate students, studying towards their PhD degrees, working on the CGRF-funded projects. Another major expense is laboratory supplies – from simple chemicals to the specialized tools needed to perform technically-demanding aspects of the research. And then there is the cost of international collaborations, of which we have a number. So although the sum awarded to my laboratory may sound like a large sum, every cent is needed to push the research forward.

How long does research take?

Another question that I am sometimes asked is why it takes so long to discover the causes, and the biochemical mechanisms that cause neuronopathic Gaucher disease. After all, the disease has been known for decades, there is an excellent therapy for type 1 Gaucher disease (that is, the form of Gaucher disease that does not affect the brain), and surely there are hundreds of researchers working on neuronopathic Gaucher disease all over the world? These are all good and relevant questions, but the answers may surprise you. First, even though the genetic cause of Gaucher disease is known, and has been known for decades, the biochemical question of why specific areas of the brain are affected in Gaucher disease, and not others, is simply unknown, as is the reason that some patients develop brain symptoms whereas others do not. As for therapy, I am sure that I have no need to tell any of you that Cerezyme (enzyme replacement), which is used for type 1 Gaucher disease patients, is simply ineffective in the brain since it cannot cross the blood-brain barrier. And finally, and this might be really surprising, but there are actually very few research laboratories working directly on neuronopathic Gaucher disease – one of the reasons for this is that the disease is very rare, and there are limited sources of research funding available from international and federal research funding agencies. This is of course where the CGRF comes in – having recognized the need to support research, the CGRF has pushed ahead and made research possible, at least in my laboratory. Moreover, funding by the CGRF has enabled us to establish a number of important collaborations with leading research laboratories all over the world.

New researchers involved

One other point before I get into the nitty-gritty of my research. I actually foresee a significant increase in the involvement and recruitment of new researchers into the neuronopathic Gaucher research area. In January 2011, I had the honor of chairing the first ever Gordon conference specifically devoted to the study of lysosomal storage diseases – for those of you not in the know, Gaucher disease belongs to a family of genetic diseases known as lysosomal storage diseases, and 180 researchers and students gathered together in Galveston, Texas, to discuss the latest advances. You should also be aware that Gordon conferences are considered the premier research conferences in the world, and the fact that the Gordon conference organization saw fit to sponsor this new conference provided significant new momentum for the field in general. The discussions at the conference were lively, and based on the large numbers of discussions that members of my laboratory had with other participants, I believe that issues related to understanding the pathological mechanisms at play in neuronopathic Gaucher disease will be pushed to the forefront of lysosomal disease research in the coming years. The importance of Gaucher disease research will also be strengthened by the recently-discovered genetic relationship between some forms of Gaucher disease and Parkinson’s disease. This is not the place to go into this issue in any more detail, but the neuroscience community is much more aware of neurological aspects of Gaucher disease than they were even five years ago. This has to be good for the research field.

My research

Let’s now get down to some of the details of my research. When I was first funded by the CGRF, we had demonstrated an important connection between changes in calcium levels and the death of nerve cells – this research is all published, and you can find links to the work via the CGRF web page (www.cgrf.org). Suffice to say that all of this work was performed using cultured cells, that is to say, nerve cells which we isolated from mice (or rat) brain, and grew in a culture dish in an incubator. The reason we worked on cultured cells, rather than on more advanced models, was because no advanced models were available. This has changed recently, and our research will now be able to address areas that could not have previously been tackled.

A mouse model is generated

A huge breakthrough came in 2007 when Dr. Stefan Karlsson, in Sweden, generated a mouse model of neuronopathic Gaucher disease. A mouse model is basically a genetically-manipulated mouse that resembles, to some extent, a human disease, and allows issues to be examined that could not be studied otherwise. For instance, new therapies are invariably tested first on mouse models of human diseases, before they can be tested on human patients. Dr. Karlsson generously made his mouse available to researchers worldwide, including to my laboratory. Now that we had this mouse, we were able to pursue research directions that had been impossible beforehand. For instance, Einat Vitner, one of the two graduate students currently supported by the CGRF, was able to show changes in levels of a molecule called ‘cathepsin’ in the brains of the mice. The release of cathepsins from cells in the brain is consistent with a model of brain dysfunction known as neuroinflammation, which interestingly, has been shown to occur in a number of other lysosomal storage diseases. Another research area was to examine which specific areas of the brain were affected in the mouse. This study was performed by the other graduate student, Tamar Farfel-Becker, who defined, for the first time, the progression of some of the neuropathological changes. Remarkably, she found that some areas which are affected might be able to provide an explanation for some of the symptoms found in children. For example, an area known as the substantia nigra reticulata was affected, and this area is known to play an important role in some of the eye movement problems observed in children (for those of you really interested in this work, it was just published in the distinguished journal, Human Molecular Genetics). These examples of some of our results lead me into a discussion of what we are planning to do over the next two and a half years of our funding.

Three major research areas

We are working on three major research areas. First, we want to understand why certain areas of the brain are affected in the disease, and of no less importance, why certain areas are not affected. If we could understand this, we might be able to make predictions about the kind of therapies that are needed. Second, we want to understand the process that I mentioned above, namely neuroinflammation, in disease progression. As I also mentioned, neuroinflammation has been observed in a number of other brain diseases, and also in other lysosomal storage diseases, meaning that lessons learned, and tools available from some of these other studies might be applicable to neuronopathic Gaucher disease. Finally, we want to take advantage of the two goals above to try to discover new therapeutic options. For instance, there are many common drugs that can be used to treat neuroinflammation – might these be useful to ameliorate disease symptoms in the mouse, and then possibly in humans? I should say that so far this approach has not been successful in the mouse that we received from Dr. Karlsson – however, there is a caveat in the use of the Karlsson mouse inasmuch as it only lives in the laboratory for a relatively short period (2-3 weeks), meaning that the window of opportunity for treatment is fairly limited.

A mouse is a mouse – NOT REALLY

This is one of the reasons that the CGRF has also funded attempts by myself and two colleagues in the Weizmann Institute, who are experts in mouse genetics, to make a new mouse model. I am unable to go into detail at this stage, but I am confident that we will have something exciting to report soon.

Is there cause for optimism?

So this is where we are to date. Is there cause for optimism? Yes. New researchers are being attracted to the field. One mouse model is available and others are on the way. Neuroscientists are becoming interested in Gaucher disease research. Links are being found between Gaucher disease and other lysosomal storage diseases, and also Parkinson’s disease. Are we close to finding a cure? Well, certainly nearer a cure than a few years ago, but much more basic research is still required before therapies will be available. How long will this take? And to that question, I must honestly say that we have no idea. Scientific discoveries normally occur due to the right environment being established for ideas to develop and come to fruition, and due to funding being available to put these ideas into practice. I can only say that my laboratory is doing its utmost to understand what is going on in the disease, and to take these findings along the path that will lead to a cure. And none of this would be possible without the wonderful support of the CGRF, and for this I express my deep gratitude.