A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase
- Christineh N. Sarkissian*,
- Zhongqi Shao†,
- Françoise Blain†,
- Rosalie Peevers†,
- Hongsheng Su†,
- Robert Heft†,
- Thomas M. S. Chang‡, and
- Charles R. Scriver*,§
- *Departments of Biology, Human Genetics, and Pediatrics, McGill University, and Debelle Laboratory, McGill University-Montreal Children’s Hospital Research Institute, 2300 Tupper Street, A-717, Montreal, QC, H3H 1P3, Canada; †IBEX Technologies, Inc., 5485 rue Paré, Montreal, QC, H4P 1P7, Canada; and ‡Artificial Cells and Organs Research Centre, McGill University, Montreal, QC, H3G 1Y6, Canada
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Communicated by Arno G. Motulsky, University of Washington, Seattle, WA (received for review October 5, 1998)
Abstract
Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an identified chemical cause of impaired cognitive development. Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effective treatments of a genetic disease. However, compliance with dietary treatment is difficult and when it is for life, as now recommended by an internationally used set of guidelines, is probably unrealistic. Herein we describe experiments on a mouse model using another modality for treatment of PKU compatible with better compliance using ancillary phenylalanine ammonia lyase (PAL, EC 4.3.1.5) to degrade phenylalanine, the harmful nutrient in PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine monooxygenase (EC 1.14.16.1), which is deficient in PKU. PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid, a harmless metabolite. We describe (i) an efficient recombinant approach to produce PAL enzyme, (ii) testing of PAL in orthologous N-ethyl-N′-nitrosourea (ENU) mutant mouse strains with HPA, and (iii) proofs of principle (PAL reduces HPA)—both pharmacologic (with a clear dose–response effect vs. HPA after PAL injection) and physiologic (protected enteral PAL is significantly effective vs. HPA). These findings open another way to facilitate treatment of this classic genetic disease.
Footnotes
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↵ § To whom reprint requests should be addressed at: Debelle Laboratory, McGill University-Montreal Children’s Hospital, 2300 Tupper Street, A-721, Montreal QC, H3H 1P3, Canada. e-mail: mc77{at}musica.mcgill.ca.
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Abbreviations: ENU, N-ethyl-N′-nitrosourea; PKU, phenylketonuria; HPA, hyperphenylalaninemia; PAL, l-phenylalanine ammonia lyase; PAH, human l-phenylalanine hydroxylase.
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A Commentary on this article begins on page 1811.
- Copyright © 1999, The National Academy of Sciences
