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2013 - CTS 2013 Congress


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Oral Communications 9

20.1 - Liver-directed cell transplantation improved serum and brain phenylalanine and neurotransmitter imbalances in a phenylketonuria (PKU) murine model

Presenter: Kristen, Skvorak, Pittsburgh, United States
Authors: Kristen J. Skvorak1,2,3,4,5,6,7, Kenneth Dorko1,2,3,4,5,6,7, Marc C. Hansel1,2,3,4,5,6,7, Veysel Tahan1,2,3,4,5,6,7, Fabio Marongiu1,2,3,4,5,6,7, Roberto Gramignoli1,2,3,4,5,6,7, Erland Arning1,2,3,4,5,6,7, Teodoro Bottiglieri1,2,3,4,5,6,7, K. Michael Gibson1,2,3,4,5,6,7, Stephen C. Strom1,2,3,4,5,6,7

Liver-directed cell transplantation improved serum and brain phenylalanine and neurotransmitter imbalances in a phenylketonuria (PKU) murine model

Kristen J. Skvorak1,2,3,4,5,6,7, Kenneth Dorko1,2,3,4,5,6,7, Marc C. Hansel1,2,3,4,5,6,7, Veysel Tahan1,2,3,4,5,6,7, Fabio Marongiu1,2,3,4,5,6,7, Roberto Gramignoli1,2,3,4,5,6,7, Erland Arning1,2,3,4,5,6,7, Teodoro Bottiglieri1,2,3,4,5,6,7, K. Michael Gibson1,2,3,4,5,6,7, Stephen C. Strom1,2,3,4,5,6,7

1Medical Genetics, University of Pittsburgh, Pittsburgh, PA, United States; 2Pharmacology, Toxicology, and Therapeutics, Kansas University Med. Center, Kansas City, KS, United States; 3Pathology, University of Pittsburgh, Pittsburgh, PA, United States; 4Biomedical Sciences, University of Cagliari, Cagliari, Italy; 5Laboratory Medicine / Pathology, Karolinska Institutet, Stockholm, Sweden; 6Metabolic Disease, Baylor Research Institute, Dallas, TX, United States; 7Clinical Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, United States

Introduction:PKU (OMIM 261600) is one of the most common inborn errors of metabolism (IEM) with an incidence of 1:16,000 in the USA. The disorder is characterized by deficiency of the phenylalanine hydroxylase (PAH) enzyme, the rate limiting step in phenylalanine (Phe) catabolism. Importantly, Phe is a precursor of tyrosine, which is catabolized to form dopamine (DA). Chronic elevation of Phe in the body, and most importantly the brain, is responsible for PKU pathophysiology (mental retardation, seizures, growth delay). A special Phe-restricted diet can improve Phe imbalance and prevent most severe phenotypes with good compliance, however some patients still endure frequent hospitalizations and persistent cognitive defects. Partial correction of another IEM mouse model by hepatic transplantation of allogeneic hepatocytes [1, 2]and human amnion epithelial cells (hAEC) [3, 4]despite low functional engraftment provided proof-of-principle for these studies. Methods: Neonatal PAH-/- mice were given 3 direct hepatic injections of 1x106 syngeneic mouse hepatocytes (HTx) or hAEC (hAEC-Tx) during the first 10 days of life (DOL). Some animals given early HTx were also given a single splenic-directed HTx (2x106 cells) after 21 DOL. Animals were maintained on normal mouse diet and were sacrificed at 1 or 3 months for analysis. Results: Phe was severely elevated above wild type in the sera and brains of PAH-/- mice. HTx resulted in a 25% reduction in Phe levels in the sera of PAH-/- females while males were not improved. Human AEC-Tx also reduced Phe 25% in females despite fewer total cells being transplanted. Phe in the sera of untreated female PKU mice was >35% higher than untreated males, which masked post-Tx male results. Importantly, amino acids in the brain showed multiple improvements following transplant, and no sex difference was apparent. Phe levels in PKU-HTx mice were reduced up to 75% while PKU-hAE-Tx mice were normalized. Additional brain amino acids, including those that can act as neurotransmitters, were normalized in PAH-/- animals after HTx. DA metabolites (DOPAC, 3-MT, HVA) and DA turnover (DOPAC+HVA/DA) were disrupted in PAH-/- brains, though DA and tyrosine were unaffected. HTx normalized 3-MT/DA, suggesting DA release was improved. DOPAC was improved ~35% and DA turnover was improved ~25%, some to a level similar to wild type, though statistical significance was not achieved. Conclusions: HTx and hAE-Tx were able to significantly reduce brain Phe in PAH-/- animals and in the sera of PAH-/- females. The discrepancy between male and female mouse sera Phe is likely unique to the model, as this has not been reported in patients. Importantly, in addition to reduction of brain Phe levels following transplant, multiple other amino acids and neurotransmitters were normalized after HTx. Metabolites along the dopamine pathway, dopamine turnover, and dopamine release were also improved. Therefore, cell therapies may be a viable option for PKU.

[1]        Skvorak K.J., et al: Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD). Biochimica Biophysica Acta 2009, 1792:1004-1010.
[2]        Skvorak K.J., et al: Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease. Molecular Therapy 2009, 17:1266-1273.
[3]        Skvorak K.J., et al: Placental stem cell correction of murine intermediate maple syrup urine disease. Hepatology 2013, 57:1017-1023.
[4]        Skvorak K.J., et al: Improved bioenergetic and neurotransmitter profiles following human amnion epithelial cell transplant in intermediate maple syrup urine disease mice. Molecular Genetics Metabolism 2013, In Press.


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