Update: September 2011

Thanks to the ongoing support of the Rotary Club of Pennant Hills and the NSW PKU Association, I am pleased to report on behalf of the research team at the Children’s Hospital at Westmead that our research continues to pick up momentum. There are two main areas on which we have been focusing:

Could a “personalized” approach to treating particular PKU gene mistakes (mutations) be developed?
About 10% of individual with PKU have a so-called nonsense PKU gene mutation, where the mistake causes the PKU enzyme to prematurely stop being made beyond the point of the mistake in the gene. This results in a shortened PKU enzyme that is either unstable and falls apart altogether, or which is otherwise nonfunctional. Such nonsense mutations are often associated with more severe PKU, where dietary phenylalanine tolerance is markedly reduced.

Research in other genetic disorders has shown that there are a number of drugs, related to a particular class of antibiotic, which can trick the cell machinery to “read through” the premature stop, allowing a full length enzyme to be made. We have applied some of these drugs in a cell culture system in the test tube to see whether we could induce the production of full length PKU enzyme that might be functional. Gladys Ho, a PhD student in the laboratory who is close to completing her studies, has indeed been able to show that for a number of these nonsense mutations we can make full-length enzyme that has its functional ability partially restored. This offers a potential form of therapy for a proportion of PKU individuals who have nonsense mutations in the gene.

A major problem at present though is that most of the drugs that can be used as “read through” therapy are toxic, particularly affecting kidney function, and so cannot be used to treat patients. However, we are aware that a number of new safe “read through” drugs are being developed, and when such drugs become available we will be well placed to test them out in our testing system.

Can a genetically modified probiotic be used to treat PKU?
As many readers will know, for some time now we have been working towards the development of a genetically modified probiotic that could be used to treat PKU. I had previously reported that XingZhang Tong, a postdoctoral research scientist in our laboratory had been able to successfully engineer a probiotic bug (Lactococcus) to make an alternative enzyme, PAL, which is able to breakdown phenylalanine. He has been able to induce this Lactococcus organism to produce good amounts of functional enzyme. He continues to tweak the system to improve the efficiency of activity and stability of the GM PAL.

To be able to test this new form of therapy for PKU we needed to import a PKU mouse from the US. We now have the PKU mouse colony well established in the lab. Through the generous support of the Australian Rotary Health Research Fund and the very hard work of the Rotary Club of Pennant Hills, we were able to recruit an enthusiastic young researcher, Naz Al-Hafid, into the group earlier this year, who is undertaking a PhD with us to study our new GM Lactococcus in the mouse model for PKU. She has been on a steep learning curve, learning how to handle the feisty critters, as well as becoming adept at all the components of the study, such as blood collection from the mice, putting little plastic tubes into their food pipes so that she can administer the precise daily dose of Lactococcus, working up all the techniques for measuring phenylalanine and tyrosine in mouse blood, culturing the Lactococcus, being able to accurately quantify it, as well as a myriad of other things you don’t want to know about!

We’re pleased to say that in the last month she has begun the experiments in mice where she is feeding the GM Lactococcus to our PKU mice. This is a very labour-intensive part of the project, and fortunately Tong is on hand to very ably assist her in these studies. It is too early to make any statements about possible benefit at this stage, but hopefully in the next 6 months or so we will be able to give a preliminary report of the outcome of our initial studies in the PKU mice.