China 
Africa 
Explore chapters and articles related to this topic
Biocatalytic Nanoreactors for Medical Purposes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Oscar González-Davis, Chauhan Kanchan, Rafael Vazquez-Duhalt
Phenylketonuria is an inborn error of amino acid metabolism caused by phenylalanine hydroxylase deficiency (Kim et al., 2004). Phenylalanine hydroxylase is a non-heme, iron-containing protein that catalyzes the conversion of phenylalanine to tyrosine and is responsible for the catabolism of most of the dietary phenylalanine. In addition to phenylalanine hydroxylase, phenylalanine ammonia-lyase from plants is being developed for the treatment of Phenylketonuria. This plant enzyme has some advantages when compared with phenylalanine hydroxylase: It does not require cofactors for degrading phenylalanine, the product trans-cinnamic acid is converted to benzoic acid in the liver, which is then excreted via the urine, and it is more stable (Hosking and Gray, 1982).
Glossary of scientific and technical terms in bioengineering and biological engineering
Published in Megh R. Goyal, Scientific and Technical Terms in Bioengineering and Biological Engineering, 2018
Phenylketonuria (PKU) is a hereditary disorder that results in reduced production of the liver enzyme phenylalanine hydroxylase. This substance is involved in the breakdown of phenylalanine in food to tyrosine. Without a modified diet, affected infants will develop severe, irreversible brain damage.
Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
To sum up it can be expected that in the future more effective therapies may be available for treating LSDs. In this connection, the enzyme substitution therapy for treating Phenylketonuria (PKU) which has been recently developed by BioMarin Pharmaceutical Inc. should be mentioned. PKU is an autosomal recessive metabolic genetic disorder that results from mutations of the phenylalanine hydroxylase (PAH) gene and is detectable during the first days of life—in the most cases via newborn screening. PHA catalyzes in presence of the cofactor tetrahydrobiopterin the first step in phenylalanine (Phe) metabolism the conversion of this essential amino acid to tyrosine. If left untreated, an accumulation of phenylalanine in the blood and brain may cause behavioral problems, seizures, intellectual disabilities, and irreversible brain damage. Until recently, the only cure is a strict life-long low Phe diet that keeps plasma Phe levels within a range of 2 to 6 mg/dL. On May 6, 2019, BioMarin Pharmaceutical Inc. announced that the European Commission (EC) has granted marketing authorization for Palynziq® (pegvaliase injection). Pegvaliase is approved for PKU patients aged 16 and older who were not able to keep their Phe levels within the recommended range by so far available treatment options. Pegvaliase is the PEGylated recombinant form of phenylalanine ammonia lyase (PAL) from the cyanobacterium Anabaena variabilis that breaks down Phe to trans-cinnamic acid and ammonia. The results of a successful long-term phase 3 clinical trial program (PRISM) have been published by Thomas et al. (2018). BioMarin also expects to submit an investigational new drug application (IND) and/or a clinical trial application (CTA) to the US FDA for its BMN 307 pre-clinical gene therapy product for the treatment of PKU in the second half of 2019. BMN 307 consists among others of a AAV vector, containing the DNA sequence that encodes the functional phenylalanine hydroxylase enzyme, deficient in PKU patients, gene therapies are treated in more detail in Chapter 21. Isabella et al. (2018) developed an alternative therapeutic strategy in that they used synthetic biology to develop a live bacterial therapeutic; they engineered Escherichia coli Nissle (SYNB 1618) to express genes encoding Phe-metabolizing enzymes. Experiments with animals suffering from PKU revealed that this genetically modified probiotic reduced blood Phe concentrations significantly; for similar experiments with the probiotic E. coli Nissle, see Crook et al. (2019).
Gene Editing: A View Through the Prism of Inherited Metabolic Disorders
Published in The New Bioethics, 2018
The inherited metabolic disorders arise when a mutation in a given gene results in a deficiency of the related enzyme. The majority of these conditions are inherited in an autosomal recessive manner, whereby both the maternally inherited and paternally inherited copy of the given gene must harbour a mutation for the disease to manifest. In the usual situation this means that both parents are heterozygous carriers of the condition, i.e. they each carry one mutated copy of the gene and one ‘healthy’ copy. Thus a deficiency of the enzyme phenylalanine hydroxylase caused by mutations in the PAH gene gives rise to the condition phenylketonuria (PKU), associated with pathologically high phenylalanine levels as this amino acid cannot be converted to tyrosine. Untreated, PKU results in significant progressive damage to the central nervous system, manifesting with microcephaly, developmental delay and significant cognitive impairment. PKU is eminently treatable with dietary phenylalanine restriction, and detection via newborn screening permits treatment to be commenced before damage occurs. Many of the metabolic disorders, however, carry a devastating prognosis, for example mucopolysaccharidosis type III (Sanfilippo syndrome) which is caused by deficiency of one of the several lysosomal enzymes that degrade complex macro-molecules (the glycosaminoglycans), with the result that these macro-molecules accumulate in different tissues of the body including the brain and cause a relentlessly progressive neurodegenerative disorder, with childhood onset dementia and significantly curtailed life-expectancy.