Alternative therapies to address the unmet medical needs of patients with phenylketonuria

Abstract

Standard therapy for phenylketonuria (PKU), the most common inherited disorder in amino acid metabolism, is an onerous phenylalanine-restricted diet. Adherence to this stringent diet regimen decreases as patients get older, and this lack of adherence is directly associated with cognitive and executive dysfunction and psychiatric issues. These factors emphasize the need for alternative pharmacological therapies to help treat patients with PKU. Sapropterin dihydrochloride is a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase that in pharmacological doses can stabilize and increase residual enzyme activity in some patients with PKU. About one-third of all patients with PKU respond to oral sapropterin. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Phase I and II trials have shown that injectable recombinant Anabaena variabilis PAL produced in Escherichia coli conjugated with PEG can reduce phenylalanine levels in subjects with PKU. The most frequently reported adverse events were injection-site reactions, dizziness and immune reactions. Additionally, oral administration of PAL and delivery of enzyme substitution therapies by encapsulation in erythrocytes are being investigated. Novel therapies for patients with PKU appear to be options to reduce phenylalanine levels, and may reduce the deleterious effects of this disorder.

Keywords:

• executive function
• phenylalanine ammonia lyase
• phenylketonuria
• sapropterin

Declaration of interest

N Longo receives clinical trial grant support from BioMarin Pharmaceutical Inc. and is an Advisor for BioMarin and Codexis, Inc. USA and N Blau receive grant support for clinical research from and act as advisors for Merck KGaA, Germany and Codexis, Inc., USA. Writing assistance was utilized in the preparation of this paper, it was carried out by Karl Zawadzki, PhD (Health Interactions, San Francisco), and supported by BioMarin Pharmaceutical, Inc., Novato, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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