Current and Promising PKU therapies

The challenge of adhering to the low-Phe diet is a major reason why researchers are looking for alternate and supportive therapies. The goals of this research range from improving the taste and variety of low-Phe foods in an effort to improve adherence, to finding a cure for PKU so that diet restrictions would no longer be required. The therapies being studied fit into the following three categories:

  • Drugs approved by the U.S. Food and Drug Administration (FDA)
  • Medical foods
  • Experimental gene replacement and enzyme substitution therapies that have yet to be approved for use

FDA-approved drugs for PKU

Sapropterin therapy (BH4; tetrahydrobiopterin; sapropterin; Kuvan®) Studies have shown that taking daily pills or a powder of sapropterin lowers and stabilizes blood Phe levels in some people with PKU. Sapropterin is available by prescription and is meant to be used in addition to the low-Phe diet. Sapropterin is not effective for everyone. To determine if sapropterin therapy will work for you, your doctor will ask you to take it for a trial period to determine its effectiveness for you.

Some people who take sapropterin are able to safely modify their diet with the help of their doctor and dietitian. This is done by increasing the intake of Phe with carefully measured amounts of dietary Phe from products such as dried egg yolks. In this circumstance, the person will have increased blood Phe monitoring throughout the process to establish when their new Phe threshold is met. The doctor and dietitian will then adjust the person’s diet to reflect the amount of Phe that they are now able to eat while still controlling their blood Phe levels. [Singh et al. 2008]

This process is not something a person can safely do without the help of his or her clinic team. The first step is to find out if you respond to sapropterin. Then speak to your doctor about whether you might be able to adjust your diet safely.

Medical foods

Large neutral amino acid (LNAA) therapy (PreKUnil, NeoPhe, PheBLOC)

LNAA therapy aims to decrease the amount of Phe entering the circulation and the brain by increasing the amount of other essential amino acids. By flooding your body with these other amino acids, more of them will get through your blood-brain barrier (BBB), which will reduce the amount of Phe that reaches your brain. Several formulations of LNAA are commercially available. In theory, LNAA therapy might be useful for all people with PKU, but at present it is only recommended for older teens and adults as its safety and effectiveness for younger PKU patients are unknown.

Glycomacropeptide (GMP)

GMP is a protein derived from goat milk during cheesemaking that is almost free of Phe. Some people with PKU think it has a better taste than current medical formulas. Research shows that it may provide a more easily digestible form of vitamins and minerals that your body can use more effectively.

Experts believe that if more and better-tasting low-Phe protein options became available, patients with PKU would be more likely to adhere to the low-Phe diet. Some PKU products containing GMP, such as BetterMilk™, are already on the market. And more PKU products containing GMP are expected to become available soon.

Still-To-Be-Approved Experimental Gene Replacement and Enzyme Substitution Therapies


Enzyme substitution therapy (PEG-PAL)

In enzyme substitution therapy for PKU, an external source of enzyme activity (PEG-PAL) is given to the patient to make up for the deficient PAH enzyme. This enzyme substitution enables Phe to be broken down, thereby decreasing blood Phe levels. Results of a Phase 1 human clinical trial showed substantial blood Phe reductions with no reported serious safety concerns. Clinical trials with a larger population of PKU patients receiving varying doses of PEG-PAL are currently underway.

Hepatocyte transplantation

PAH, which is the enzyme that is deficient in PKU, resides in liver cells (hepatocytes). A promising line of research involves replacing some of the defective liver cells with liver cells that have normal PAH activity, causing Phe levels to drop to a normal range.

Gene therapy

The idea behind gene therapy is to introduce a functional and stable PAH gene into those who have PKU in order to supplement or replace the defective PAH gene. This would provide a cure for PKU. However, the technology required is still experimental and the safety issues are substantial. Several laboratories have achieved varying degrees of success in correcting PAH deficiency in mice using gene therapy, but there are no existing human trials.