RESEARCH OVERVIEW
The last five years have seen great strides in finding ways to improve treatment for phenylketonuria, or PKU. Below is a brief synopsis of work being done by leading researchers across the country to improve PKU treatment options.

COFACTOR THERAPY
The first drug for PKU was approved by the FDA in December 2007. Kuvan improves Phe tolerance in some PKU patients by increasing BH4 in the body, the co-factor to the PAH enzyme that does not work in those with PKU. Kuvan essentially stimulates the PAH enzyme, which in turn starts to process Phe. While Kuvan does not replace the diet, it can improve Phe tolerance 2-3 fold in certain PKU patients that are responsive to the Kuvan loading test.

ENZYME SUBSTITUTION
In enzyme substitution, researchers discovered an alternate enzyme found in plants and bacteria that can breakdown Phe. In order for the enzyme (PAL) to work, a protector (PEG), or “coater” needs to be placed around the enzyme to help it from breaking down quickly in the body and protecting the enzyme from the immune response. The result, is PEG-PAL, an injectible medicine that has shown to lower Phe levels in PKU mice. The first FDA study of PEG-PAL began in 2008, and hopes to show a decrease in Phe levels in PKU patients. Successful phase 1 results were reported in June, 2009.

LARGE NEUTRAL AMINO ACIDS
LNAA’s also shows promising results to treat people with PKU. Essentially, LNAA’s compete with Phe for transport into the brain. By introducing other LNAA’s in the diet, the passage of Phe is blocked to the brain, thereby decreasing brain Phe levels. There are currently four products available:  Lanaflex, PreKUnil, NeoPhe and PheBloc. LNAA’s do not replace the diet, but they may be good adjunct therapy for those who have a poorly controlled diet.

GLYCOMACROPEPTIDE
Glycomacropeptide (GMP) is a whey-based protein that is produced when making cheese. It is the only known dietary protein that contains a minimal amount of Phe. Foods made with GMP provide an alternative to the amino acid medical foods currently required in the PKU diet. GMP foods have also been found to significantly lower Phe levels in blood and plasma.
An expanded study of GMP foods with PKU patients is slated to begin in January 2010 pending FDA approval.

GENE AND CELL THERAPY
Gene therapy is an ideal treatment for treating PKU because it would be able to transfer a functional PAH enzyme into the liver cells. Unfortunately, the challenge in gene therapy has been the immune response. While gene therapy has worked in curing PKU in mice, immunosuppressant medications have also had to be used to maintain the correction. Some new techniques have shown
promise though, including recombinant adenovirus-associated
vectors (rAAV), and using a heterologous tissue approach.
rAAV’s have been shown to cause less immune response,
maintain a longer correction and be safer. Current research
includes injecting rAAV’s into the muscle versus the liver.