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

Abstract

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.

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

“…Although with these limitations, fibroblasts, if combined with other models, may be functional in identifying new pathways, confirming pathogenic mechanisms, or validating the efficacy of therapeutic molecules, as we recently reported (45).…”

“…Yeast is also a valuable system to screen for compounds with therapeutic potential to treat mitochondrial diseases as a “repurposing” strategy. Two research teams applied this approach in the context of OPA1 mutations ( 44 , 45 ). In the first screening, a collection of 1,600 repurposed drugs has been used and five compounds were able to suppress the lethality in restrictive conditions caused by a GTPase mutation of MSP1 in S. pombe .…”

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

“…Five of them also ameliorated, to a different extent, the pathological OXPHOS phenotypes of Opa1 null mouse embryo fibroblasts (MEFs), that express the human OPA1 isoform 1, bearing R445H and D603H mutations, associated with DOA-plus and DOA, respectively. The analysis in patient's fibroblasts bearing the same mutations allowed to identify the tolfenamic acid, a non-steroidal anti-inflammatory drug, as the most promising therapeutic compound and to propose the repurposing of this drug in a clinical trial for neurodegenerative diseases associated with OPA1 mutations [267].…”

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

“…A recent work used a "drug repositioning" approach to identify FDA-approved molecules, which are able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. The combined use of yeast, mouse embryonic fibroblasts (MEFs), and human model has allowed an accurate selection of the screened molecules: Twenty-six drugs were effective in the rescue of the oxidative growth phenotype in yeast strains carrying mgm1 mutations; six of them, acting on mtDNA instability, have been used to treat Opa1 deleted MEFs, and some of them showed a positive effect on energetic metabolism and/or mitochondrial morphology; the final validation on patient's fibroblasts has led to the selection of the tolfenamic acid as the most promising compound to be used in a clinical trial for patients with OPA1 mutations [200].…”