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Perspective interview - Aurora Martinez

Perspective interview - Aurora Martinez

2014 PKU Perspectives Aurora Martinez

Prof Aurora Martinez tells us why chaperones are still in fashion

Prof Aurora Martinez1 provided delegates with an update on the search for new and better chaperone candidates, at the 2014 Annual Multidisciplinary European PKU Symposium. Pharmacological chaperones are chemicals with the ability to restore some, or all function to an enzyme affected by a gene mutation. These have great potential as therapies for PKU and other IEMs, caused by missense mutations.

Prof Martinez began working with phenylalanine hydroxylase (PAH) as a postdoctoral researcher. Today, now a Professor of Biomedicine at the University of Bergen (Norway) and director of the Biorecognition research group she continues to work with this challenging protein. She told us: 'I joined a group that was already working on PKU and initially I was looking at the expression of the protein, trying to understand the effect of the mutations on the action of the enzyme; the relationship between genotype and phenotype.'

Misfolding holds the key

'We realized that most mutations that lead to IEMs do so by causing a misfolding of the protein, which destabilizes it and results in a loss of activity, Prof Martinez explained. ‘PAH is a very complex protein that is responsible for a complex reaction. Mutations can cause conformational changes that have a significant effect on the enzyme function and lead to faster degradation of the enzyme itself. We have now found more than 700 mutations that are known to cause some form of HPA'

How then, we asked, did this evolve into a hunt for pharmacological chaperones and why are these important? The Professor replied: 'We found that it is possible to recover part of the lost activity by using small compounds; these are the chaperones that recover the protein. They can renature and stabilize the native conformation and delay degradation, increasing the lifetime of the enzyme.'

Success of sapropterin

Prof Martinez began by saying ‘One of the best known small molecule chaperones is the naturally occurring cofactor BH4. Exogenous BH4, is now licensed as sapropterin for use as a therapy for PKU. However, it needs to be remembered that BH4is itself a co-substrate in the reaction, so it has other effects. It can accelerate the reaction. All reactions in the body have their own homeostasis so if you try to increase the concentration of a compound above a threshold level there will be other reactions that will try to degrade it.

'In addition', she continued 'the chaperone effect of BH4 is only seen in 20—30% of patients, as it is dependent on the nature of their genotype and the resulting misfolding. There are many patients with misfolding that cannot be helped using BH4. For these two reasons, BH4 although effective, is not the ideal chaperone and so we continue to look for alternatives.'

The perfect chaperone

How, we asked, was the search going. Prof Martinez replied: 'We studied BH4 for many years, as this really was the 'Proof of concept' for pharmacological chaperones. From this, we started our search for other compounds, not found in vivo, that could have a better chaperone effect without affecting the reaction in other ways. We had a first generation of compounds that worked very well but had limitations.  We found there were issues with solubility and specificity.  They also affected other aromatic amino acid hydroxylases.

'For our second generation compounds we changed our approach, this time screening for compounds that could work with BH4, looking for synergistic effects. This time we were screening for compounds that would bind to different parts of PAH to those which BH4 binds, in the hope that the two compounds together would have a greater stabilizing effect. This is possible because if this were achieved, the new chaperone could potentially stabilize PAH while allowing BH4 to act normally so the reaction proceeds as it should.

'We are now in the final steps of in vitro studies where we have combined a formulation of compounds with BH4 and we are seeing that this is in fact possible. With these second generation compounds we have been looking for effects on other hydroxylases from the start.

'There are a lot of things to take into account at each step of the investigational process and many more steps to go before we reach even the pre-clinical stage but it is promising and I hope that we will see new pharmacological chaperones that are soluble, effective and specific.'

Beyond diet

Why is it important to be looking for new therapies? The professor said: 'It is a success story to have a diet that prevents PKU. That is for sure. But the diet is not perfect, not a good life for everyone. For these people we need to continue doing research to find therapies that will work for them. There is a spectrum of patients with very different levels of blood-Phe and very different effects of the disease.

'My belief is that there will be a series of possibilities, more than one drug, because the patients are very different. There are some who, even without treatment, can relax the diet without any consequences for a number of days and others for whom it is essential that they are on strict diet continuously. Therefore I think the therapeutic possibilities will be more or less adapted to the patient.'

The future of PKU treatment

What then were her hopes for the future for PKU treatment? 'What I envisage is a future of personalized therapy where you will choose the drug or the approach that fits best to the patient’s genotype,' said Prof Martinez. 'I can understand that, for economic reasons, a company would be very interested in finding a single drug which would, in varying doses, suit all genotypes but I don’t think that this is realistic.

'However, I think it is possible, given the different therapeutic approaches currently being investigated, that we would be able to better adapt to the three categories of patients, for example: the very mild, the mild and the classic PKU, and each of these three classes will have a therapy. And the diet will always be there for all.'


1 - Prof Aurora Martinez (Department of Biomedicine, University of Bergen, Bergen, Norway)