Idebenone increases chance of stabilization/recovery of visual acuity in <i>OPA1</i>‐dominant optic atrophy

Romagnoli, Martina; Morgia, Chiara La; Carbonelli, Michele; Vito, Lidia Di; Amore, Giulia; Zenesini, Corrado; Cascavilla, Maria Lucia; Barboni, Piero; Carelli, Valerio

doi:10.1002/acn3.51026

Cited by 32 publications

(23 citation statements)

References 16 publications

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“…Nevertheless, patients’ results are more encouraging: a pilot study on seven DOA patients documented encouraging results after 1-year of idebenone administration, with some improvement of visual function [ 246 ]. A recent retrospective cohort study investigated the effect of off-label idebenone administration on visual outcome in a DOA group of 87 patients, demonstrating that the treatment was significantly associated with stabilization/recovery of visual acuity [ 247 ].…”

Section: “One-size-fits-all” Approachesmentioning

confidence: 99%

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.

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Section: “One-size-fits-all” Approachesmentioning

confidence: 99%

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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“…Table 1 summarizes all the therapeutic approaches used up to date. [197] OPA1 coenzyme Q10 No evidence for a significant benefit in dominant optic atrophy (DOA) patients [198] idebenone In 74 of 87 DOA treated patients, an increased visual acuity was observed after at least 7 months of administration [199] tolfenamic acid…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

Nottia

Verrigni

Torraco

et al. 2021

Genes

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Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On the other hand, following the fusion process, mitochondria appear as longer and interconnected tubules, which enhance the communication with other organelles. Both fission and fusion are carried out by a small number of highly conserved guanosine triphosphatase proteins and their interactors. Disruption of this equilibrium has been associated with several pathological conditions, ranging from cancer to neurodegeneration, and mutations in genes involved in mitochondrial fission and fusion have been reported to be the cause of a subset of neurogenetic disorders.

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“…Unfortunately, there is currently no established treatment for OPA1-linked diseases. It has been reported that idebenone treatment induces some degrees of visual improvement in OPA1 -DOA patients ( 23 , 24 ), whereas it presents a limited therapeutic effect in a mouse model of OPA1-related DOA, strictly correlated to NQO1 expression ( 25 ). Even if there is an ongoing effort to genetically correct OPA1 mutations ( 26 ), gene therapy is still far from clinical use ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

Aleo

Dotto

Fogazza

et al. 2020

Human Molecular Genetics

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OPA1 mutations are the major cause of Dominant Optic Atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a ‘drug repurposing’ approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying twenty-six drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA (mtDNA) instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts (MEFs) expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients’ fibroblasts, allowing to select the most effective molecules. Our current results are instrumental to rapidly translating the findings of this drug repurposing approach into clinical trial for DOA and other neurodegenerations caused by OPA1 mutations.

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Idebenone increases chance of stabilization/recovery of visual acuity in OPA1‐dominant optic atrophy

Cited by 32 publications

References 16 publications

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

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