Research Blog

Prepared by: Professor John Christodoulou, Head, PKU Clinic
Contact phone number: 02 9845 3452 

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PKU Research at the Children’s Hospital at Westmead
Update: January 2010

We had a busy year in 2009, and continue to make steady progress in our PKU research activities.

PKU Gene Studies:
We continue to offer screening of the PKU (phenylalanine hydroxylase; PAH) gene to any of the patients we see in our clinic.  PhD student, Gladys Ho, is performing this work.  We anticipate that by identifying the combination of mistakes (mutations) in the PAH gene, we will be better able to predict the level of dietary restriction that will be needed.  In addition, there are some mutations that allow us to predict that some individuals (perhaps up to a third of PKU patients currently on diet) will be responsive to the essential cofactor, tetrahydrobiopterin (BH4).  This is important information, because once BH4 becomes more easily available in Australia, we will be in a position to identify those individuals who are likely to be BH4 responsive for immediate access to it.

On that front, we understand that the company trying to get BH4 approved and licensed in Australia submitted a formal application to the Federal agency responsible for reviewing such applications in December, and we hope that it will approved in the first quarter of this year, although there is no guarantee about this at present.

So, if you or your PKU child has not had genetic testing done yet and would like this to be done, please discuss this with your PKU doctor.  The genetic testing is available as part of a research project based at the Children’s Hospital at Westmead.  We have information sheets and consent forms to become involved in this research, and we are happy to make these available to you through your PKU doctor.

Progress in the Development of a PAL Probiotic Therapy:
Readers will recall from previous newsletters that we have been working on a new therapy for PKU, namely the provision of an alternate enzyme, phenylalanine-ammonia lyase (PAL) that is able to break down excess amounts of phenylalanine.  A combined research effort in Canada and the US has developed a chemically modified form of PAL that is delivered to patients by regular injection.  Whilst this is a great step forward in the development of a novel treatment approach to PKU, our view is that for many individuals regular injections (it is not clear at this stage how frequently the injections will need to be given) of the PAL enzyme would not be acceptable. 

Our approach is to create a genetically modified (GM) probiotic to produce PAL.  This PAL could then be delivered through a regular oral drink of a Yakhult type of preparation. If it works, phenylalanine released from dietary protein in the intestine would be broken down before it is even absorbed into the bloodstream, and this should translate to improved protein tolerance with better control of blood phenylalanine levels.

With the generous support of a research grant from the Australian Rotary Health Fund (sponsored by the Rotary Club of Pennant Hills), and financial support from the Rotary Club of Liverpool (Greenaway), we have been able to develop this idea.  We are pleased to report that we now have working PAL being made by a probiotic called Lactococcus.  We are currently making adjustments to the genetic regulatory machinery so that we can maximize the efficiency with which PAL is produced by the Lactococcus probiotic.

The next step will be to test out our new PKU therapy in a PKU mouse.  There is a commercially available mouse that has a severe mutation in the mouse version of the PKU gene, which in turn results in very high blood phenylalanine levels.  There are significant costs involved in importing the mouse to Australia, establishing a PKU mouse colony and then performing the trial of the GM Lactococcus.  Unfortunately, at present we do not have the funds to establish the mouse colony and perform the therapeutic trial, and so we are currently unable to progress to the next stage.  We are currently in the process of trying to obtain additional funding from a number of sources, and if successful in our fundraising activities, we will be able to perform the initial mouse studies over the next 12 months. 

We will keep you informed of progress on all these research fronts, so stay tuned for the next installment!

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