Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease.
Maple syrup urine disease (MSUD; OMIM 248600) is an inborn error of metabolism of the branched chain alpha-ketoacid dehydrogenase (BCKDH) complex that is treated primarily by dietary manipulation of branched-chain amino acids (BCAA). Dietary restriction is lifelong and compliance is difficult. Liver transplantation significantly improves outcomes; however, alternative therapies are needed. To test novel therapies such as hepatocyte transplantation (HTx), we previously created a murine model of intermediate MSUD (iMSUD), which closely mimics human iMSUD. LacZ-positive murine donor hepatocytes were harvested and directly injected (10(5) cells/50 microl) into liver of iMSUD mice (two injections at 1-10 days of age). Donor hepatocytes engrafted into iMSUD recipient liver, increased liver BCKDH activity, improved blood total BCAA/alanine ratio, increased body weight at weaning, and extended the lifespan of HTx-treated iMSUD mice compared to phosphate-buffered saline (PBS)-treated and untreated iMSUD mice. Based on these data demonstrating partial metabolic correction of iMSUD in a murine model, coupled to the fact that multiple transplants are possible to enhance these results, we suggest that HTx represents a promising therapeutic intervention for MSUD that warrants further investigation.
Skvorak
Kristen J
KJ
Department of Human Genetics, University of Pittsburgh, Pennsylvania, USA. kjskvorak@gmail.com
Paul
Harbhajan S
HS
Dorko
Kenneth
K
Marongiu
Fabio
F
Ellis
Ewa
E
Chace
Donald
D
Ferguson
Carolyn
C
Gibson
K Michael
KM
Homanics
Gregg E
GE
Strom
Stephen C
SC
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000637:transplantation*; D008099:Liver / Q000378:metabolism; D008375:Maple Syrup Urine Disease / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)