*8.3. Enzyme Therapy*

In 1980, phenylalanine ammonia lyase (PAL) was recognized as a potential treatment for PKU, because of its ability to metabolize excess Phe into less toxic products, trans-cinnamic acid, and ammonia, regardless of genotype. Enzyme replacement therapy and enzyme substitution are two other treatment strategies adopted. In enzyme replacement therapy, a functional PAH enzyme and its co-factor BH4 are delivered by orthotopic liver transplantation. Enzyme replacement is a daunting process that is useful only for the few PKU patients who need a liver transplant. Enzyme substitution by PAL is less troublesome and does not require the co-factor, because it acts directly as a substitute for deficient PAH. When injected into humans, PAL triggers a host-immune response and is degraded by proteases. To overcome that problem, PAL is conjugated with polyethylene glycol (PEG-PAL). PEG-PAL, now called pegvaliase, is in clinical trials. In 2018, pegvaliase (trade name Palynziq®) was approved by the FDA in the USA. However, severe adverse events were frequently observed in the clinical trials. The safety of pegvaliase is also a concern during pregnancy [115–117].
