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Perspective interview - K Michael Gibson

Perspective interview - K Michael Gibson

2014 PKU perspectives K. Michael Gibson

Barriers to progress

Prof Gibson introduced his talk to the EPG symposium by saying the idea of using NPAAs was, ‘a little out-there!’ So where, we asked, did the idea come from.

‘A colleague of mine, Bill [William] Zinnanti, really first pioneered this idea in maple syrup urine disease (MSUD) mice. He took norleucine (Nle), an analogue of the normal branched-chain AA leucine (Leu) and he fed it to MSUD mice to see if he could lower the levels of Leu and other branched-chain AAs in their brains. It worked! He was able to show that it could lower the levels of the target compounds in their brains. He also showed that it improved the behavior of the mice and some of the other neurological markers. He published his results in a very nice paper in 2009  and this gave me the idea that if you can do this with MSUD mice then you could perhaps do it with other large AA neuropathies, like PKU.

‘Both Leu and Phe are large neutral AAs (LNAA) and both move across the BBB on the same transporters from the periphery into the brain so I thought there must be a way to target Phe and reduce it in the brain. If we found it then that would just give us a revolutionary approach to treat PKU mice (Pahenu2 mice) and then eventually, hopefully, patients. So we’ve adapted Bill Zinnanti’s idea and taken it into PKU mice. Currently, we’re exploring the suitability of a number of different compounds using the PKU animal model.’

From having a bright idea to getting started in the laboratory can take a very long time. Did this process, we wondered, prove to be a challenge. ‘We really started this line of research about 2010. Yes, it took us a little while to get ourselves set up and we had to seek funding, but we were really very fortunate to gain the support of the National PKU Alliance (USA). They gave us seed funding for a graduate student, Kara Vogel (the first author of the paper we published in 2013 ) to work for two years and really get things going. This was vital as it allowed us to generate some preliminary data which then allowed us to go to other granting agencies, especially the National Institutes of Health, USA (NIH).’

Mice work

Working with animals can present huge challenges in terms of experimental design; how did the professor decide the best way to use the mice?

‘Initially it took us some time to get the animal model together’ Prof Gibson said. ‘A big decision was whether we would give the test compounds intravenously, as injections or orally. We chose oral administration. Although this is slower and more inconvenient than the other methods we wanted to make the study as pre-clinically useful as we could. We felt that this method could shorten the time it would take to move our data from the mouse model to the patient. For four weeks we fed the PKU-mice with a selected diet and then we looked at their brains, focusing on the levels of AAs.

What compounds showed promise? ‘Kara Vogel found an old reference on a compound called N-methyl-aminoisobutyrate (MAIB) which is an esoteric compound that’s not usually in the human body. It’s actually supposed to be a specific inhibitor for small AA transport into the brain from the periphery. We found it gave a very nice result on Brain-Phe levels in the mouse model and this has opened up a number of avenues for further research. We are continuing to look at other compounds related to MAIB.

‘The challenge,’ explained Prof Gibson, ‘is to find a compound that is very specific for Phe, and we’re very close to that. But, Phe and tyrosine (Tyr) are very close in structure, they have very similar “saturation constants” let’s call it for movement across from the periphery to the brain and so everything we’ve tried so far has still had a slight effect on Tyr. This is a problem because Tyr is the precursor of dopamine, one of the major monoamine neurotransmitters. The search is still on to find a compound that will compete with Phe but have limited action with regard to the transport of all the other LNAAs.’

A model is just an imitation of the real thing

The value of using animal models is questioned by many people who are not involved with scientific research. How much of a role have animals played in Prof Gibson’s work?

‘The mouse model is absolutely pivotal. All my research has completely moved into mouse models. When I took a position at Oregon Health Science University (USA) in 1999 I developed a mouse model [Aldh5a1-deficient mice] of a different genetic disease [4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria] . Pre-clinical animal studies using this mouse allowed us to try new therapeutic approaches which, to date, have generated two clinical studies that have been funded by the NIH.’

The real thing

Recruiting patients to participate in any clinical study can be a challenge but with IEMs there is the added problem that the numbers of suitable patients can be very low. How did one effectively move to the next step, clinical studies?

‘This is a major stumbling block. One solution that we use in the USA is to limit initial pilot trials to a single center. This way, we can hopefully get enough patients with the disorder to come to one site.’

How important are links between researchers and patient groups for recruiting patients to clinical studies, we asked. ‘Patient groups and the parent support groups are fundamentally important. They are able to make bridges between researchers and patients. They keep their members informed about research developments. Today, a lot of these groups have registries for patients which are Research Advisory Board approved. This allows us to contact physicians that have enlisted on these registries, tell them about a study and see if they have any patients that are suitable and who would possibly be willing to be involved.’

Michael Gibson

Professor of Clinical Pharmacology
Washington State University
Spokane, United States