Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene-specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR-181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR-181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno-associated viral vector (AAV) that harbors a miR-181a/b inhibitor (sponge) sequence (AAV2/8-GFP-Sponge-miR-181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO-P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR-181a/b downregulation modulates the level of the mitochondrial fission-related protein Drp1 and rescues the mitochondrial fragmentation in RHO-P347S photoreceptors. Overall, these data support the potential use of miR-181a/b downregulation as an innovative mutation-independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene-specific therapeutic approaches.

miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases / Carrella, Sabrina; Di Guida, Martina; Brillante, Simona; Piccolo, Davide; Ciampi, Ludovica; Guadagnino, Irene; Garcia Piqueras, Jorge; Pizzo, Mariateresa; Marrocco, Elena; Molinari, Marta; Petrogiannakis, Georgios; Barbato, Sara; Ezhova, Yulia; Auricchio, Alberto; Franco, Brunella; De Leonibus, Elvira; Surace, Enrico Maria; Indrieri, Alessia; Banfi, Sandro. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4684. - (2022). [10.15252/emmm.202215941]

miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases

Auricchio, Alberto;Franco, Brunella;Surace, Enrico Maria;
2022

Abstract

Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene-specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR-181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR-181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno-associated viral vector (AAV) that harbors a miR-181a/b inhibitor (sponge) sequence (AAV2/8-GFP-Sponge-miR-181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO-P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR-181a/b downregulation modulates the level of the mitochondrial fission-related protein Drp1 and rescues the mitochondrial fragmentation in RHO-P347S photoreceptors. Overall, these data support the potential use of miR-181a/b downregulation as an innovative mutation-independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene-specific therapeutic approaches.
2022
miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases / Carrella, Sabrina; Di Guida, Martina; Brillante, Simona; Piccolo, Davide; Ciampi, Ludovica; Guadagnino, Irene; Garcia Piqueras, Jorge; Pizzo, Mariateresa; Marrocco, Elena; Molinari, Marta; Petrogiannakis, Georgios; Barbato, Sara; Ezhova, Yulia; Auricchio, Alberto; Franco, Brunella; De Leonibus, Elvira; Surace, Enrico Maria; Indrieri, Alessia; Banfi, Sandro. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4684. - (2022). [10.15252/emmm.202215941]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/898768
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