Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria.

Autor:	Lai C; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA. Electronic address: clai@dicerna.com., Pursell N; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Gierut J; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Saxena U; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Zhou W; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Dills M; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Diwanji R; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Dutta C; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Koser M; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Nazef N; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Storr R; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Kim B; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Martin-Higueras C; Hospital Universitario de Canarias, Centre for Biomedical Research on Rare Diseases (CIBERER), Universidad La Laguna, Tenerife, Spain., Salido E; Hospital Universitario de Canarias, Centre for Biomedical Research on Rare Diseases (CIBERER), Universidad La Laguna, Tenerife, Spain., Wang W; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Abrams M; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Dudek H; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA., Brown BD; Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA. Electronic address: bbrown@dicerna.com.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2018 Aug 01; Vol. 26 (8), pp. 1983-1995. Date of Electronic Publication: 2018 Jun 15.
DOI:	10.1016/j.ymthe.2018.05.016
Abstrakt:	Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end-stage renal disease. One promising strategy to treat PHs is to reduce the hepatic production of oxalate through substrate reduction therapy by inhibiting liver-specific glycolate oxidase (GO), which controls the conversion of glycolate to glyoxylate, the proposed main precursor to oxalate. Alternatively, diminishing the amount of hepatic lactate dehydrogenase (LDH) expression, the proposed key enzyme responsible for converting glyoxylate to oxalate, should directly prevent the accumulation of oxalate in PH patients. Using RNAi, we provide the first in vivo evidence in mammals to support LDH as the key enzyme responsible for converting glyoxylate to oxalate. In addition, we demonstrate that reduction of hepatic LDH achieves efficient oxalate reduction and prevents calcium oxalate crystal deposition in genetically engineered mouse models of PH types 1 (PH1) and 2 (PH2), as well as in chemically induced PH mouse models. Repression of hepatic LDH in mice did not cause any acute elevation of circulating liver enzymes, lactate acidosis, or exertional myopathy, suggesting further evaluation of liver-specific inhibition of LDH as a potential approach for treating PH1 and PH2 is warranted. (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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