title: Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model.
abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disorder using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 ± 156 (sham transplanted) to 338 ± 157 μmol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 ± 4 (sham transplanted) to 5.3 ± 1.9 μmol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may be required for greater disease correction; however these studies show promising results for cell transplantation biochemical correction of a metabolic disorder.
authors.affiliation: Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children's Hospital, Flemington Road, Parkville, VIC 3052, Australia. nicole.buck@mcri.edu.au
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Buck
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Pennell
authors.forename: Leonie R
authors.initials: LR
authors.lastname: Wood
authors.forename: James J
authors.initials: JJ
authors.lastname: Pitt
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Allen
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Peters
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000601:surgery*; D000818:Animals; D002469:Cell Separation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005333:Fetus / Q000166:cytology*; D008099:Liver / Q000166:cytology* / Q000196:embryology*; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D008765:Methylmalonyl-CoA Mutase