Radiothon 2018/2019

For over a decade The NSW PKU association have been generously funding PKU research at The Children’s Hospital at Westmead. Our commitment to ensuring Dr Minal Menezes and her team have all the resources to do high quality research has seen opportunities to pursue some exciting new therapies for PKU. They are currently trailing two potential therapies for PKU.

Two of the four current PKU research projects that we are funding are:

"Stop the Nonsense" - Potential therapeutic for PKU
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 called phenylalanine hydroxylase deficiency (PAH), that is either unstable and falls apart altogether, or which is otherwise non-functional. Such nonsense mutations are often associated with more severe PKU, where dietary phenylalanine tolerance is markedly reduced.
A potential therapy for PKU is the ability to restore a functional PAH enzyme. Research in other genetic disorders has shown that there are a number of drugs, which can trick the cell machinery to "read through" the premature stop, allowing a full length enzyme to be made. A major problem at present though is that most of these 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 of a new safe "read through" drug, which has been clinically approved for many years and has been used for its function as an anti-inflammatory antiallergic agent. Once we have successfully established the efficacy of the drug in a cell based system, the next step would be a pre-clinical trial. This will demonstrate the translational capacity of our research in identifying an effective and safe therapeutic treatment for PKU patients.

"When Protein get too sticky" - Anti-aggregation agent is a potential therapeutic for treatment for PKU
The second area of our research focuses on a subset of missense mutations of the PAH gene are known to cause aggregation of the PAH protein i.e. makes the protein sticky. This is hypothesised to be a result of misfolding of the mutant polypeptide. Arginine is a commonly used safe supplement but surprisingly also has protein stabilizing effects. Preliminary cell based studies with arginine have shown anti-aggregation effect, leading us to hypothesize that it might constitute a promising therapeutic agent in specific cases of PKU. Further investigations are in progress to assess the effect of arginine on PAH protein levels and function.

Cheers
Bridie