MiR‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases. Issue 11 (4th October 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 14:Issue 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-04
• Subjects: inherited retinal diseases -- miR‐181 -- mitochondria -- photoreceptor -- therapy; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202215941
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The application of gene‐specific approaches for the treatment of inherited retinal diseases (IRDs) is hampered by their broad genetic heterogeneity. Modulation of the expression of miR‐181a/b in the retina represents a promising gene‐independent therapeutic strategy for these conditions. miR‐181a/b downregulation slows down retinal degeneration in an in vivo model for a dominant form of IRD, i.e., the transgenic RHO‐P347S mouse. miR‐181a/b downregulation ameliorates the retinal phenotype of an animal model for a recessive form of IRD, i.e., the rd10 mouse. Photoreceptor cells of RHO‐P347S mice show an early mitochondrial dysfunction that is counteracted by miR‐181a/b downregulation. Abstract : The application of gene‐specific approaches for the treatment of inherited retinal diseases (IRDs) is hampered by their broad genetic heterogeneity. Modulation of the expression of miR‐181a/b in the retina represents a promising gene‐independent therapeutic strategy for these conditions.