rPEG-PAL is Potential Treatment for PKU

foodPhenylketonuria (PKU) is caused by a genetic deficiency in the enzyme phenylalanine hydroxylase which metabolizes dietary phenylalanine to tyrosine. When phenylalanine accumulates, it is converted to phenyl ketones, including phenylpyruvate and phenylacetate. Excess phenylalanine in the blood also saturates the large neutral amino acid transporter and depletes other large neutral amino acids in the brain, disrupting brain development and leading to mental retardation. Although there is no cure for PKU, if detected early it can be controlled by strictly limiting dietary intake of phenylalanine and supplementing intake of tyrosine. This restrictive diet essentially excludes milk and dairy products, meat, fish, chicken, eggs, beans and nuts which all contain very high levels of phenylalanine. Fruits, vegetables, breads and pastas also contain some phenylalanine and cannot be eaten freely. Soft drinks and foods containing the sweetener aspartame must also be avoided. Most experts believe that the diet should be adhered to throughout life but this can be very difficult, especially during adolescence and early adulthood.

A study published in the December 30th issue of the journal PNAS now suggests that a new treatment may allow people with PKU to eat a much less restricted diet. The study, which was carried out in a mouse model that mimics PKU, evaluated the ability of PEGylated phenylalanine ammonia lyases (PEG-PALs) from four different species to lower phenylalanine levels in both vascular space and brain tissue over a >90 day period. The most effective lyase therapeutically was one produced by the cyanobacterium, Anabaena variabilis. This lyase had the highest stability rather than the highest specific activity, indicating the importance of protein stability for in vivo efficacy. BioMarin Pharmaceutical Inc have begun a phase I clinical trial to assess the safety and tolerability of recombinant PEG-PAL in people with PKU.