ArticlePloS one2017
Formulation and PEGylation optimization of the therapeutic PEGylated phenylalanine ammonia lyase for the treatment of phenylketonuria.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Italian national consensus statement on management and pharmacological treatment of phenylketonuria.Orphanet journal of rare diseases · 2021Pooled it
- Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria.Clinical and translational science · 2021Trial
- Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study.Orphanet journal of rare diseases · 2018Trial
- Minicells derived fromApplied and environmental microbiology · 2026Article
- Phenylalanine homeostasis in metabolic disorders: epidemiological trends, pathophysiological mechanisms, and clinical treatment.Frontiers in endocrinology · 2026Review
- Synthetic closed-loop gene circuit for phenylalanine regulation.Nucleic acids research · 2025Article
- Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program.Molecular genetics and metabolism reports · 2024Article
- Protein substitutions as new-generation pharmanutrition approach to managing phenylketonuria.Clinical and experimental pediatrics · 2023Article
- A method for phenylalanine self-monitoring using phenylalanine ammonia-lyase and a pre-existing portable ammonia detection system.Molecular genetics and metabolism reports · 2023Article
- Sex-Gender-Based Differences in Metabolic Diseases.Handbook of experimental pharmacology · 2023Review
- Moving Protein PEGylation from an Art to a Data Science.Bioconjugate chemistry · 2022Article
- Modeling the cognitive effects of diet discontinuation in adults with phenylketonuria (PKU) using pegvaliase therapy in PAH-deficient mice.Molecular genetics and metabolism · 2022Article
- Microreactor equipped with naturally acid-resistant histidine ammonia lyase from an extremophile.Materials advances · 2022Article
- Automated prediction of site and sequence of protein modification with ATRP initiators.PloS one · 2022Article
- Article
- Improvement of a synthetic live bacterial therapeutic for phenylketonuria with biosensor-enabled enzyme engineering.Nature communications · 2021Article
- Purification of Modified Therapeutic Proteins Available on the Market: An Analysis of Chromatography-Based Strategies.Frontiers in bioengineering and biotechnology · 2021Review
- Directed evolution of Anabaena variabilis phenylalanine ammonia-lyase (PAL) identifies mutants with enhanced activities.Chemical communications (Cambridge, England) · 2020Article
- Erythrocytes as Carriers: From Drug Delivery to Biosensors.Pharmaceutics · 2020Review
- Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria.Journal of inherited metabolic disease · 2020Observational
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phenylketonuria (PKU) is a genetic metabolic disease in which the decrease or loss of phenylalanine hydroxylase (PAH) activity results in elevated, neurotoxic levels of phenylalanine (Phe). Due to many obstacles, PAH enzyme replacement therapy is not currently an option. Treatment of PKU with an alternative enzyme, phenylalanine ammonia lyase (PAL), was first proposed in the 1970s. However, issues regarding immunogenicity, enzyme production and mode of delivery needed to be overcome. Through the evaluation of PAL enzymes from multiple species, three potential PAL enzymes from yeast and cyanobacteria were chosen for evaluation of their therapeutic potential. The addition of polyethylene glycol (PEG, MW = 20,000), at a particular ratio to modify the protein surface, attenuated immunogenicity in an animal model of PKU. All three PEGylated PAL candidates showed efficacy in a mouse model of PKU (BTBR Pahenu2) upon subcutaneous injection. However, only PEGylated Anabaena variabilis (Av) PAL-treated mice demonstrated sustained low Phe levels with weekly injection and was the only PAL evaluated that maintained full enzymatic activity upon PEGylation. A PEGylated recombinant double mutant version of AvPAL (Cys503Ser/Cys565Ser), rAvPAL-PEG, was selected for drug development based on its positive pharmacodynamic profile and favorable expression titers. PEGylation was shown to be critical for rAvPAL-PEG efficacy as under PEGylated rAvPAL had a lower pharmacodynamic effect. rAvPAL and rAvPAL-PEG had poor stability at 4°C. L-Phe and trans-cinnamate were identified as activity stabilizing excipients. rAvPAL-PEG is currently in Phase 3 clinical trials to assess efficacy in PKU patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.