Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria
| العنوان: | Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria |
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| المؤلفون: | Kelly Barrios, Bernd Hoppe, Bob D. Brown, Craig B. Langman, Ralf Rosskamp, Gema Ariceta |
| المساهمون: | Institut Català de la Salut, [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, Vall d'Hebron Barcelona Hospital Campus |
| المصدر: | Kidney International Reports Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Kidney International Reports, Vol 6, Iss 4, Pp 1088-1098 (2021) Scientia |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Small interfering RNA, Other subheadings::Other subheadings::/antagonists & inhibitors [Other subheadings], Lactate dehydrogenase A, Urinary system, 030232 urology & nephrology, lactate dehydrogenase A, Nutritional and Metabolic Diseases::Metabolic Diseases::Metabolism, Inborn Errors::Carbohydrate Metabolism, Inborn Errors::Hyperoxaluria, Primary [DISEASES], 030204 cardiovascular system & hematology, Pharmacology, lcsh:RC870-923, nedosiran, Excretion, Primary hyperoxaluria, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Clinical Research, Enzymes and Coenzymes::Enzymes::Oxidoreductases::Alcohol Oxidoreductases::Lactate Dehydrogenases [CHEMICALS AND DRUGS], medicine, Otros calificadores::Otros calificadores::/antagonistas & inhibidores [Otros calificadores], education, education.field_of_study, Metabolisme, Errors congènits de, biology, business.industry, enzimas y coenzimas::enzimas::oxidorreductasas::alcohol oxidorreductasas::lactato deshidrogenasas [COMPUESTOS QUÍMICOS Y DROGAS], Epigenètica, medicine.disease, lcsh:Diseases of the genitourinary system. Urology, small interfering RNA, fenómenos genéticos::regulación de la expresión génica::epigénesis genética::silenciamiento génico::interferencia por ARN [FENÓMENOS Y PROCESOS], Inhibidors enzimàtics, Nephrology, enfermedades nutricionales y metabólicas::enfermedades metabólicas::alteraciones congénitas del metabolismo::trastornos congénitos del metabolismo de los carbohidratos::hiperoxaluria primaria [ENFERMEDADES], Renal physiology, biology.protein, Genetic Phenomena::Gene Expression Regulation::Epigenesis, Genetic::Gene Silencing::RNA Interference [PHENOMENA AND PROCESSES], Creatine kinase, business, primary hyperoxaluria, Nedosiran |
| الوصف: | Introduction 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. Graphical abstract |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2468-0249 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::22b6de5a9935a8f3c3b0e0a068586382Test http://europepmc.org/articles/PMC8071644Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....22b6de5a9935a8f3c3b0e0a068586382 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24680249 |
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