MIR-181A/B INHIBITION AS A NEW STRATEGY FOR MITOCHONDRIAL DISEASE TREATMENT
type: CreativeWork
description: Mitochondrial diseases (MDs) are a group of rare inherited disorders caused by defective oxidative phosphorylation (OXPHOS) and defined by a wide range of clinical phenotypes. MDs show extreme genetic heterogeneity, which makes the development of efficient treatments particularly difficult. Indeed, despite recent progress, no effective therapies are currently available. Gene/mutation-independent approaches targeting downstream affected pathways are highly needed, considering their genetic heterogeneity. In this context, microRNAs (miRNAs) emerge as promising therapeutic agents due to their ability to simultaneously regulate different pathways. In particular, miR-181a and miR-181b (collectively referred to as miR-181a/b) are two miRNAs involved in mitochondrial processes, and their downregulation has recently been demonstrated to exert a protective action on different MD models associated with neuronal degeneration. This study further investigates the effects of miR-181a/b inhibition in MD contexts and evaluates the feasibility of translating this approach into clinical applications by testing a therapeutic technology to achieve long-term miR-181a/b downregulation in vivo. We assessed the efficacy of our therapeutic approach in different MD models: the Ndufs4 knockout (KO) mouse, which serves as a Leber’s Hereditary Optic Neuropathy (LHON) and Leigh syndrome (LS) model, two of the most prevalent MDs, and the rotenone-induced mouse model, an additional in vivo model of LHON. Notably, our results demonstrate that the downregulation of miR-181a/b consistently ameliorates various phenotypes across all tested conditions. Furthermore, the therapeutic strategy targeting miR-181a/b in vivo exhibited a highly safe and specific profile, paving the way for clinical application.
abstract: Mitochondrial diseases (MDs) are a group of rare inherited disorders caused by defective oxidative phosphorylation (OXPHOS) and defined by a wide range of clinical phenotypes. MDs show extreme genetic heterogeneity, which makes the development of efficient treatments particularly difficult. Indeed, despite recent progress, no effective therapies are currently available. Gene/mutation-independent approaches targeting downstream affected pathways are highly needed, considering their genetic heterogeneity. In this context, microRNAs (miRNAs) emerge as promising therapeutic agents due to their ability to simultaneously regulate different pathways. In particular, miR-181a and miR-181b (collectively referred to as miR-181a/b) are two miRNAs involved in mitochondrial processes, and their downregulation has recently been demonstrated to exert a protective action on different MD models associated with neuronal degeneration. This study further investigates the effects of miR-181a/b inhibition in MD contexts and evaluates the feasibility of translating this approach into clinical applications by testing a therapeutic technology to achieve long-term miR-181a/b downregulation in vivo. We assessed the efficacy of our therapeutic approach in different MD models: the Ndufs4 knockout (KO) mouse, which serves as a Leber’s Hereditary Optic Neuropathy (LHON) and Leigh syndrome (LS) model, two of the most prevalent MDs, and the rotenone-induced mouse model, an additional in vivo model of LHON. Notably, our results demonstrate that the downregulation of miR-181a/b consistently ameliorates various phenotypes across all tested conditions. Furthermore, the therapeutic strategy targeting miR-181a/b in vivo exhibited a highly safe and specific profile, paving the way for clinical application.
author: VOLPE, MARIAGRAZIA
language: eng
keywords: mitochondria, mitochondrial disease, LHON, Leigh syndrome, microRNA, miRNAs, Settore BIOS-08/A - Biologia molecolare
date published: 2024-12-19
date modified: 2026-07-27T20:18:58Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1126195