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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorAriceta Iraola, Gema
dc.contributor.authorBarrios, Kelly
dc.contributor.authorBrown, Bob D.
dc.contributor.authorHoppe, Bernd
dc.contributor.authorRosskamp, Ralf
dc.contributor.authorLangman, Craig B.
dc.date.accessioned2021-12-16T06:44:07Z
dc.date.available2021-12-16T06:44:07Z
dc.date.issued2021-04
dc.identifier.citationAriceta G, Barrios K, Brown BD, Hoppe B, Rosskamp R, Langman CB. Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria. Kidney Int Reports. 2021 Apr;6(4):1088–98.
dc.identifier.issn2468-0249
dc.identifier.urihttp://hdl.handle.net/11351/6691
dc.descriptionRNA interference; Lactate dehydrogenase A; Primary hyperoxaluria
dc.description.abstractIntroduction 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. Methods 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. Results 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. Conclusion 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.
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofseriesKidney International Reports;6(4)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectMetabolisme, Errors congènits de
dc.subjectInhibidors enzimàtics
dc.subjectEpigenètica
dc.subject.meshHyperoxaluria, Primary
dc.subject.meshLactate Dehydrogenases
dc.subject.mesh/antagonists & inhibitors
dc.subject.meshRNA Interference
dc.titleHepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1016/j.ekir.2021.01.029
dc.subject.decshiperoxaluria primaria
dc.subject.decslactato deshidrogenasas
dc.subject.decs/antagonistas & inhibidores
dc.subject.decsinterferencia por ARN
dc.relation.publishversionhttps://doi.org/10.1016/j.ekir.2021.01.029
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[Ariceta G] Servei de Nefrologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Barrios K, Brown BD, Rosskamp R] Dicerna Pharmaceuticals, Inc., Lexington, Massachusetts, USA. [Hoppe B] Dicerna Pharmaceuticals, Inc., Lexington, Massachusetts, USA. German Hyperoxaluria Center Cologne/Bonn, Bonn, Germany. [Langman CB] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
dc.identifier.pmid33912759
dc.identifier.wos000639562600025
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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