Mito Target Project

[Guest]

Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)

Please could you tell us a little bit about the MitoTarget Project and Trophos’ role in the project?

The MitoTarget Project was a project funded by the European Commission, under their FP7 programme. It was funding for a call published in 2007.

It was a project we started nearly 5 years ago by assembling a consortium of investigators. It had two objectives:

to promote a clinical trial of our mitochondrial-targeting compound – Olesoxime

to further explore the hypotheses that mitochondrial function is the key ingredient in neurodegenerative diseases.

Essentially, there were two goals of the research, one was basic research and one was clinical research.

How did the MitoTarget Project fit with Trophos’ main aims?

Trophos was created to take a novel approach to identifying molecules that would be effective in neurodegenerative diseases. There are no particular targets that had been validated, or shown to be safe and effective, in clinical studies for neurodegenerative diseases.

We took a founding scientist’s model, which is based on the identification of protein neurotrophic factors to identify small molecules that have the same neuroprotective ability. The protein neurotrophic factors were thought to have clinical potential, but their developments had met with a number of difficulties.

Our idea was if it works to pick out protein factors from a big brain soup, then why not use it to screen small molecules that could be developed as drugs.

From the very beginning the idea was to find small molecules that could protect neurons and on the basis of that assay develop those drugs for different neurodegenerative diseases.

This fit also with the model of the French patient organisation called the AFM (Association Francaise contre les Myopathies). They were interested in identifying drugs to treat an orphan neurodegenerative disease called Spinal Muscular Atrophy which affects motor neurons.

How did the MitoTarget Project originate?

The project originated mainly because we are a small biotech and we have limited means. We had managed to develop our compound through to small Phase II studies, but didn’t have the means to continue to larger studies involving several hundred patients such as ALS.

We identified a call from the European Union. The European Union has a focus on trying to finance basic research that also develops small companies in areas that the EC has identified as having unmet needs, which are not met by industry. They include rare diseases, neurodegenerative diseases.

The European Union had a specific call that was in brain and aging, to try to find a new methodology to promote health in European citizens, by looking for things that prevent neurodegeneration.

It was good timing as it came at exactly the time that we had a molecule that had all the clinical and pre-clinical background. It already had the background that could support that it was safe and well-tolerated in humans for a long-term clinical trial.

At the same time, I think over the course of several years, the role of mitochondrial dysfunction had become quite prominent. There was a large amount of circumstantial evidence coming from a lot of different models.

So, we thought if we could develop a programme to evaluate in more detail the hypothesis that mitochondrial dysfunction is involved in neurodegenerative diseases from a basic research side, we could, at the same time, take this molecule that we identified that targets the mitochondria.

We had a number of assays of mitochondrial function where it looked like it should be beneficial as well as animal models of neurodegeneration where it seemed to be effective. At the end we might come up with a new paradigm for identifying novel drugs for treating neurodegenerative diseases and hopefully validate mitochondrial dysfunction as playing an important role.

Please could you give a brief introduction to neurodegenerative diseases and what was previously known about the mechanisms that cause them?

Except for some rare genetic diseases such as Spinal Muscular Atrophy, Charcot-Marie-Tooth which affects children at the very earliest stage, most neurodegenerative diseases, even if they have a genetic background, still only occur in adults or aging populations.

There is supposed to be an aging component as well as genetic components that seem to play a role in neurodegenerative diseases.

One of the things that occurs in aging is oxidative stress - mitochondrial dysfunction and metabolism are affected. That was one of the first moves that indicated that mitochondrial dysfunction may lead to a weakness in neurons that makes them susceptible to aging.

What did the MitoTarget Project add to this understanding of neurodegenerative diseases?

We looked at a number of different parameters of mitochondrial function. Mitochondria are membrane organelles, in fact they have two membranes, which are responsible for producing ATP.

These mitochondria need to be localized. They are synthesized and reproduced independently of the cell and are localized to certain parts of the cell which have a high energy demand.

We looked at a number of things. We looked at the integrity of mitochondrial membranes in different model; we looked at their ability to traffic to different parts of the cell in different neurodegenerative disease models.

We also looked at the ability of the mitochondria to undergo a process called permeability transition. This is often caused by oxidative stress or calcium overload and can lead to a rupture of the outer mitochondrial membrane. This releases protein factors which then lead to a process called active cell death, or apoptosis.

We compared and contrasted what happened in different neurodegenerative diseases. I think what we can say is that all the neurodegenerative diseases that we have explored had one or more aspects of mitochondrial dysfunctions present; but not a single one of them was really common to all neurodegenerative diseases.

Therefore, what we can say is that mitochondrial dysfunction may be a part of the mechanism of neurodegenerative diseases and for that reason will probably need eventual therapy, but they may not be the sole trigger of neurodegenerative diseases.

What impact will these results have on treating neurodegenerative diseases?

That is a good question, as like all complex diseases you may need to treat multiple mechanisms simultaneously.

For example, if you look at a complex disease like AIDS, where we now have four different therapies that target different processes of viral integration, replication, virulence etc. that combined are far more effective than any of those drugs are alone.

The thing about AIDS is that each one of those drugs was able to show some primary efficacy in its own right. That made finding combination therapies much more in line with regulatory guidelines.

Today what we see is that regulatory guidelines are only just beginning to create a path for testing multiple drugs in combination, which have different mechanisms that neither one of them has yet shown clinical proof of efficacy.

I think this is beginning now in much more severe diseases, certain cancers, tuberculosis, and in certain neurodegenerative diseases, the idea of testing drugs where there are two new clinical entities in combination, will have to be the way forward.

What are Trophos’ plans for the future?

Trophos continues to explore the activity of its compounds in other degenerative conditions that have implications of mitochondria dysfunction or where we have seen efficacy in some animal models.

For example, we have a second compound in our pipeline, called TRO40303, and it came out of the chemical strategy for Olesoxime. That molecule also targets the mitochondria.

We started studying our molecules that target mitochondria in cardiovascular disease, because it was shown, about the same time that we discovered these compounds, that mitochondrial permeability transition was a process that leads to programmed cell death in cardiomyocytes is a key to injury following a myocardial infarction.

The cardiac tissue that is deprived of oxygen starts to undergo necrosis. Then when you provide it with oxygen again, the cells that are still alive are subjected to a rapid burst of oxygen that leads to a lot of free-radical damage. That leads to permeability transitions that leads to death of cells that were originally still alive at the time that the reperfusion took place.

By blocking this permeability transition in mitochondria, you can protect cardiomyocytes from this reperfusion injury.

Initially, just to test our hypothesis that mitochondria were indeed the target of our drugs, we explored our compounds in the models of cardiac reperfusion injury and showed that they were effective.

We then decided to independently develop a second compound for that indication. That molecule is still in a clinical study, which is also funded by an FP7 project which also came up at the right time for the molecule at the right stage of development to begin testing it in humans to see if we can salvage some of the cardiac damage that can occur in patients undergoing emergency angioplasty.

We also have continued to explore the activity of Olesoxime in other neurodegenerative models. We have data coming from MitoTarget in models of Huntington’s disease and Alzheimer’s disease. We have some studies that were funded by the Michael J Fox foundation that shows some interesting effects in a model of Parkinson’s disease.

Independently with a French grant we studied the role of Olesoxime to promote neuroprotection and myelin repair in models of Multiple Sclerosis.

Our next major thrust now is to develop the means to test Olesoxime as a complementary therapy in Multiple Sclerosis. Multiple Sclerosis, while it’s considered to be largely an autoimmune or inflammatory disease of the central nervous system, one of the main problems is that even though the inflammatory process is controlled now with a large number of immune-modulatory drugs, they don’t seem to have a major impact on the disability in the patient.

That disability is due to neurodegeneration and that could be because there being a failure to repair the myelin damage. We’ve shown now in a number of pre-clinical models, in a paper that was published in January, that Olesoxime is able to actually promote the regeneration of myelin sheaths by promoting maturation of the oligodendrocytes in the brain.

We think this is a promising complementary approach that could be able to control the neurodegeneration and promote repair in multiple sclerosis. Our main aim is to take Olesoxime forward as a treatment in neurodegenerative diseases where you can begin treatment before neurodegeneration is too far advanced as may be the case in ALS.

The molecule is still in a study as well in a pediatric neurodegenerative disease known as Spinal Muscular Atrophy.

How do you think the future of understanding of neurodegenerative diseases will develop?

Well, I think there are lots of indications coming from the clinical studies in Alzheimer’s disease where they are looking at the role of amyloid plaque to trigger metabolic changes in different brain regions. The metabolic changes again may be a consequence of mitochondrial dysfunction. I think the next route forward in Alzheimer’s disease may be to find drugs to treat the metabolic changes.

Alzheimer’s disease has had enormous amounts of investment as a large number of people are suffering from Alzheimer’s disease. Thus, it is an area, while not easy, is easier than rare neurodegenerative diseases such as ALS.

Huntington’s disease is another disease with lots of investments. Family members know from a very early age that they have a risk for developing Huntington’s disease because it is a dominant, hereditary disease.

In these two areas there is a large research strategy to develop biomarkers, new diagnostic tools, new prognostic indicators as well as therapeutic interventions. I think combining all of these is really necessary to be able to get an indication that the drugs you are developing actually show some beneficial signs, because the neurodegeneration itself may take quite some time before you see the cognitive or other disabilities that are linked to the degeneration.

Would you like to make any further comments?

Trophos itself is a very small company that was founded by basic scientists and entrepreneurs who took this novel approach to neurodegenerative diseases. I think this novel approach has a large promise. It is up to us now to find which diseases would be best treated by the drugs that we’ve identified.

Where can readers find more information?

http://www.trophos.com/

About Rebecca Pruss, Ph.D., CSO of Trophos

Ms. Pruss has over 25 years experience in the pharmaceutical industry directing research and development including 16 years with major pharmaceutical companies.

Prior to joining Trophos in 2002, she was the head of exploratory research at Sanofi-Synthelabo, now Sanofi-Aventis and president and chief executive officer at Synthélabo Biomoléculaire. She has directed discovery research involving target and cell-based screening strategies. This resulted in more than a dozen compounds entering the clinic.

Previously, she was head of biomolecular screening at Synthélabo Biomoléculaire, and a senior scientist and project leader at Marion Merrell Dow.

Dr. Pruss has also served as adjunct professor in Cell Biology at the University of Cincinnati and is an invited lecturer on translational research, drug discovery and the biotech industry.

She received a Ph.D. in biological chemistry from UCLA and performed postdoctoral research in neuroimmunology and developmental neurobiology at University College London and the National Institutes of Healt. This was funded by fellowships from the Jane Coffin Childs Memorial Fund for Medical Research and NIH Pharmacology Research Associate Fellowship.

She has authored or co-authored 70 peer-reviewed publications, book chapters and invited reviews and is an inventor on over a dozen issued or published patent applications covering screening assays, novel compounds and their uses. Dr. Pruss is and has been the principle investigator on two Trophos-led EU FP7 projects, MitoTarget and MitoCare.

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I found this interview--------yet i have not totally been able to wrap my head around it (the theory/actions)------give me some time: I'll see if i can find more too add