title: Enzyme replacement therapy in ENU2 phenylketonuric mice using oral microencapsulated phenylalanine ammonia-lyase: a preliminary report.
abstract: The presence of an extensive enterorecirculation of amino acids between the intestine and the body allows the removal of systemic phenylalanine in PKU rats by oral microencapsulated phenylalanine ammonia lyase. The work presented in this article has the main goal of assessing the feasibility of yeast phenylalanine ammonia-lyase (PAL) loaded collodion microcapsules in reducing elevated plasma phenylalanine concentrations to standard levels in genetically mutated PKU mice, within a 30 day time frame. The distinguishing aspect from previous studies lies in the available animal model. Rather than artificial induction of elevated phenylalanine plasma levels, the mice representing the human phenylketonuric condition, are mutated strains which are deficient in the enzyme phenylalanine hydroxylase. The first in vivo study established a method for orally feeding microcapsules, both control and enzyme loaded, over 30 consecutive days, by mixing with soft, unripened cheese. Under this unique regime a decrease of 51.3% +/- 9.02% in phenylalanine plasma levels was observed after 23 days. Reduction in the phenylalanine plasma levels to within the desired maintenance range of 250-1000 umol/L was observed in 2 out of 4 PAL treated mice, with only 50% of the PAL dose used in previous rat studies by Chang's group. The second animal study confirmed the finding in the first in vivo study that there is no significant decrease in the plasma phenylalanine levels within the first seven days. This may be due to the severely deteriorated physical condition of the ENU mice used, the PAL enzyme preparations available or the fact that normal mice contain 10 times the amount of phenylalanine hydroxylase as compared with humans, thus requiring larger doses of PAL in order to be effective in a shorter time span.
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Safos
authors.forename: T M
authors.initials: TM
authors.lastname: Chang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003101:Collodion; D004339:Drug Compounding; D005038:Ethylnitrosourea; D005240:Feasibility Studies; D005656:Fungal Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D010650:Phenylalanine Ammonia-Lyase / Q000008:administration & dosage / Q000627:therapeutic use*; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000235:genetics; D010661:Phenylketonurias / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051381:Rats; D012248:Rhodotorula / Q000201:enzymology; D013045:Species Specificity
chemical_list: D005656:Fungal Proteins; D003101:Collodion; D010651:Phenylalanine Hydroxylase; D010650:Phenylalanine Ammonia-Lyase; D005038:Ethylnitrosourea