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Human amnion epithelial (hAE) stem cell transplant significantly improves phenotype and survival in a murine model of intermediate maple syrup urine disease (iMSUD) 

Kristen Skvorak¹, Kenneth Dorko¹, Fabio Marongiu¹, Veysel Tahan¹, Marc Hansel¹, Roberto Gramignoli¹, Erland Arning², Teodoro Bottiglieri², Qin Sun³, K. Michael Gibson⁴, Stephen Strom¹

¹Pathology, University of Pittsburgh, Pittsburgh, PA; ²Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX; ³Human & Molecular Genetics, Baylor College of Medicine, Houston, TX; ⁴Biological Sciences, Michigan Tech University, Houghton, MI, United States

MSUD (OMIM 248600) is a rare disorder of branched chain amino acid (BCAA; leucine, isoleucine, valine) catabolism caused by mutation of the branched-chain keto-acid dehydrogenase (BCKDH) enzyme complex. Treatment requires lifelong dietary restriction and compliance is variable, often resulting in catabolic crisis. Liver transplantation has greatly improved patient outcome. Previous studies verified that hepatocyte transplantation partially corrects a transgenic murine model of iMSUD, establishing that a small number of proficient cells transplanted into the liver significantly improves disease phenotype and survival (Mol. Ther. 2009, 17(7):126; Biochim Biophys Acta 2009, 1792(10):1004). Applying this rationale, human placental amnion-derived stem cells, which share many characteristics with pluripotent embryonic stem cells, were explored as an alternative to hepatocytes for use in cell transplant. During the first 10 days of life (DOL), neonates were given two direct hepatic injections of 1x10 ⁶cells. After 21 DOL, bi-weekly injections (2x10^6 cells) were administered until 35 DOL. Growth of transplanted iMSUD mice mimicked wildtype, and survival was significantly lengthened compared to untreated iMSUD. BCKDH enzyme activity was significantly improved, as well as serum and brain amino acids, at 35 and 100 DOL. A ratio of BCAA to alanine, a more representative indicator of disease status than BCAAs alone, was decreased >50% at both time points while alloisoleucine was not statistically different from unaffected controls. Neurotransmitter alterations and brain injury is characteristic of MSUD resulting from toxic accumulation of BCAAs. Importantly, brain monoamines showed improvements in hAE transplanted animals at both time points, and dopamine and serotonin turnover was normalized at 100 days. Similar to mouse hepatocytes, transplants of human AE stem cells partially corrected this mouse model of iMSUD. We propose that these placental stem cells may be an alternate to hepatocytes as therapy for MSUD, and possibly other liver-based inborn errors of metabolism.