Phenylketonuria is a genetic disorder that occurs due to a mutation in the PAH gene, resulting in reduced/no production of phenylalanine hydroxylase, an enzyme involved in the break down of phenylalanine.
Phenylalanine is used in the body to make neurotransmitters for the brain, pigment for the skin (melanin), and tyrosine. Furthermore, it is required for growth, our general health and much more. As a result of the missing/dysfunctional enzyme, there is a build-up of phenylalanine in the body which has severe consequences. Phenylketonuria is characterised with learning difficulties, behavioral issues, mental conditions, brain damage, and many other complications.
Unfortunately, there is no cure available for Phenylketonuria yet. Individuals have to follow a strict diet by reducing the consumption of foods high in phenylalanine such as soybeans, watercress, shrimp, etc. Patients often use supplements to replenish vital nutrients that are missing due to the strict diet. Tyrosine is made from Phenylalanine, so tyrosine supplements are used to increase tyrosine levels which boost brain health. Alternatively, there are drugs such as Pegvaliase that provide an enzyme substitute to metabolise phenylalanine and reduce its level in the body. All these treatments are just managing the disease, further work needs to be done for a treatment that helps with producing the enzyme itself.
A study was conducted at Oregon Health & Science University in which CRISPR was used to treat Phenylketonuria. AAV mediated CRISPR-Cas9 gene editing was performed to correct the mutation in the PAH gene of mice with Phenylketonuria. Vanillin, an NHEJ inhibitor was given at the same time to prevent NHEJ and to enhance HDR. It was found that the enzymatic activity of PAH was restored and this caused a reduction of phenylalanine in the blood, therefore showing promising results as an alternative therapy for Phenylketonuria.