Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

• Published in: Journal of inherited metabolic disease Vol. 33; no. 6; pp. 649 - 658
• Main Authors: Muntau, Ania C, Gersting, Søren W
• Format: Journal Article
• Language: English
• Published: Dordrecht Dordrecht : Springer Netherlands 01.12.2010; Springer Netherlands; Springer; Blackwell Publishing Ltd
• Subjects: Aminoacid disorders; Animals; Biochemistry; Biological and medical sciences; Diet Therapy - methods; Drug Discovery - methods; Enzyme Replacement Therapy - methods; Errors of metabolism; Human Genetics; Humans; Internal Medicine; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism, Inborn Errors - drug therapy; Metabolism, Inborn Errors - pathology; Models, Biological; Models, Molecular; Orphan Drug Production; Pediatrics; Phenylalanine - adverse effects; Phenylketonurias - diet therapy; Phenylketonurias - drug therapy; Phenylketonurias - pathology; Proteostasis Deficiencies - drug therapy; Proteostasis Deficiencies - pathology; Review; Fabry Disease; Protein Misfolding; Phenylketonuria; Lysosomal Storage Disease; Gauche Disease; Disease development; Human; Nervous system diseases; Nutrition; Patient; Metabolic diseases; Protein A; Enzymopathy; Congenital disease; Orphan drug; Genetic disease; Genetics; Models; Aminoacid disorder
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-010-9185-4

The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.