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Development of a Protease Stable Phenylalanine Ammonia Lyase as an Orally Administered Enzyme Therapy for Potential Treatment of PKU

Phenylketonuria (PKU) is caused by a mutation in phenylalanine hydroxylase (PAH), which metabolizes phenylalanine (Phe) to tyrosine. The pathophysiology of PKU is linked to the toxic effects of excess Phe in the blood and tissues, particularly the brain. Untreated PKU is associated with progressive cognitive, psychological, and behavioral issues. The only available treatments for PKU patients are a life-long, Phe-restricted diet, a universal treatment, or sapropterin, which treats only a subset of patients.
Hoskins et al. reported in 1980 that an encapsulated orally-administered Phenylalanine Ammonia Lyase (PAL) reduced blood Phe levels by 25% in a single patient, presumably by degrading Phe digested protein in the small intestine. While promising, an oral enzyme therapy was not advanced clinically. PAL from Anabaena variabilis (AvPAL) modified with polyethylene glycol was instead developed for subcutaneous injection.

Using CodeEvolver® protein engineering technologies, we generated and screened 27,232 variants of AvPAL for improved stability to the conditions in the gastrointestinal (GI) tract to develop CDX-6114, a potential oral enzyme therapy for PKU. Due to limitations of testing oral therapeutics in rodents, proof-of-concept studies were done in healthy animals with digestive systems more similar to humans. By tracking cinnamic acid formation in the monkey, it was determined that the enzyme removed therapeutically relevant amounts of Phe in the GI-tract. In conclusion, CDX-6114 is a new potential universal treatment for PKU that is expected to enter Phase I clinical trials later this year.

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