Hepatic Lactate Dehydrogenase A : An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria
Ariceta Iraola, Gema (Hospital Universitari Vall d'Hebron)
Barrios, Kelly (Dicerna Pharmaceuticals, Inc., Lexington)
Brown, Bob D. (Dicerna Pharmaceuticals, Inc., Lexington)
Hoppe, Bernd (German Hyperoxaluria Center Cologne/Bonn)
Rosskamp, Ralf (Dicerna Pharmaceuticals, Inc., Lexington)
Langman, Craig B. (Ann and Robert H. Lurie Children's Hospital of Chicago)
Universitat Autònoma de Barcelona

Fecha:	2021
Resumen:	Primary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage. LDHA inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. LDHA is mainly expressed in the liver and muscles. Nonclinical data in mice and nonhuman primates show that LDHA inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA inhibition. Based on a literature review of human LDHA deficiency, we defined the phenotype as mainly muscle-related with no liver manifestations. Healthy volunteers treated with nedosiran experienced no drug-related musculoskeletal adverse events. There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function. Phase I clinical data on nedosiran and published nonclinical data together provide substantial evidence that LDHA inhibition is a safe therapeutic mechanism for the treatment of all known types of PH.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Lactate dehydrogenase A ; Nedosiran ; Primary hyperoxaluria ; RNA interference ; Small interfering RNA
Publicado en:	Kidney International Reports, Vol. 6 (february 2021) , p. 1088-1098, ISSN 2468-0249

DOI: 10.1016/j.ekir.2021.01.029
PMID: 33912759

11 p, 1.4 MB

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