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 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts 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

Aleo, S.J., Del Dotto, V., Fogazza, M., Maresca, A., Lodi, T., Goffrini, P., et al. (2020). Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations. HUMAN MOLECULAR GENETICS, 29(22), 3631-3645 [10.1093/hmg/ddaa244].

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

Aleo, Serena J;Del Dotto, Valentina;Fogazza, Mario;Maresca, Alessandra;Ghelli, Anna;Rugolo, Michela;Carelli, Valerio;Zanna, Claudia
2020

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 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts 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
2020
Aleo, S.J., Del Dotto, V., Fogazza, M., Maresca, A., Lodi, T., Goffrini, P., et al. (2020). Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations. HUMAN MOLECULAR GENETICS, 29(22), 3631-3645 [10.1093/hmg/ddaa244].
Aleo, Serena J; Del Dotto, Valentina; Fogazza, Mario; Maresca, Alessandra; Lodi, Tiziana; Goffrini, Paola; Ghelli, Anna; Rugolo, Michela; Carelli, Val...espandi
File in questo prodotto:
File Dimensione Formato  
2021 - Aleo et al HMG.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione - Non commerciale (CCBYNC)
Dimensione 1.37 MB
Formato Adobe PDF
1.37 MB Adobe PDF Visualizza/Apri
supplementary_material_19-10-20_ddaa244.docx

accesso aperto

Tipo: File Supplementare
Licenza: Licenza per accesso libero gratuito
Dimensione 1.37 MB
Formato Microsoft Word XML
1.37 MB Microsoft Word XML Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/802061
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 13
social impact