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Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria

1
Section of Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
2
Orphan Technologies Ltd., 8640 Rapperswil, Switzerland
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(9), 2895; https://doi.org/10.3390/nu12092895
Received: 31 July 2020 / Revised: 9 September 2020 / Accepted: 18 September 2020 / Published: 22 September 2020
(This article belongs to the Section Nutrition and Metabolism)
Albeit effective, methionine/protein restriction in the management of classical homocystinuria (HCU) is suboptimal and hard to follow. To address unmet need, we developed an enzyme therapy (OT-58), which effectively corrected disease symptoms in various mouse models of HCU in the absence of methionine restriction. Here we evaluated short- and long-term efficacy of OT-58 on the background of current dietary management of HCU. Methionine restriction resulted in the lowering of total homocysteine (tHcy) by 38–63% directly proportional to a decreased methionine intake (50–12.5% of normal). Supplemental betaine resulted in additional lowering of tHcy. OT-58 successfully competed with betaine and normalized tHcy on the background of reduced methionine intake, while substantially lowering tHcy in mice on normal methionine intake. Betaine was less effective in lowering tHcy on the background of normal or increased methionine intake, while exacerbating hypermethioninemia. OT-58 markedly reduced both hyperhomocysteinemia and hypermethioninemia caused by the diets and betaine in HCU mice. Withdrawal of betaine did not affect improved metabolic balance, which was established and solely maintained by OT-58 during periods of fluctuating dietary methionine intake. Taken together, OT-58 may represent novel, highly effective enzyme therapy for HCU performing optimally in the presence or absence of dietary management of HCU. View Full-Text
Keywords: inborn error of metabolism; rare disease; tandem mass spectrometry; mouse model; enzyme replacement therapy; sulfur metabolism; homocysteine inborn error of metabolism; rare disease; tandem mass spectrometry; mouse model; enzyme replacement therapy; sulfur metabolism; homocysteine
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MDPI and ACS Style

Park, I.; Bublil, E.M.; Glavin, F.; Majtan, T. Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria. Nutrients 2020, 12, 2895. https://doi.org/10.3390/nu12092895

AMA Style

Park I, Bublil EM, Glavin F, Majtan T. Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria. Nutrients. 2020; 12(9):2895. https://doi.org/10.3390/nu12092895

Chicago/Turabian Style

Park, Insun, Erez M. Bublil, Frank Glavin, and Tomas Majtan. 2020. "Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria" Nutrients 12, no. 9: 2895. https://doi.org/10.3390/nu12092895

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