Inherited retinal diseases (IRDs) represent a frequent cause of genetic blindness. Their high genetic heterogeneity hinders the application of gene-specific therapies to the vast majority of patients. We recently demonstrated that the microRNA miR-204 is essential for retinal function, although the underlying molecular mechanisms remain poorly understood. Here, we investigated the therapeutic potential of miR-204 in IRDs. We subretinally delivered an adeno-associated viral (AAV) vector carrying the miR-204 precursor to two genetically different IRD mouse models. The administration of AAV-miR-204 preserved retinal function in a mouse model for a dominant form of retinitis pigmentosa (RHO-P347S). This was associated with a reduction of apoptotic photoreceptor cells and with a better preservation of photoreceptor marker expression. Transcriptome analysis showed that miR-204 shifts expression profiles of transgenic retinas toward those of healthy retinas by the downregulation of microglia activation and photoreceptor cell death. Delivery of miR-204 exerted neuroprotective effects also in a mouse model of Leber congenital amaurosis, due to mutations of the Aipl1 gene. Our study highlights the mutation-independent therapeutic potential of AAV-miR204 in slowing down retinal degeneration in IRDs and unveils the previously unreported role of this miRNA in attenuating microglia activation and photoreceptor cell death.

AAV-miR-204 Protects from Retinal Degeneration by Attenuation of Microglia Activation and Photoreceptor Cell Death / Karali, M.; Guadagnino, I.; Marrocco, E.; De Cegli, R.; Carissimo, A.; Pizzo, M.; Casarosa, S.; Conte, I.; Surace, E. M.; Banfi, S.. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - STAMPA. - 19:(2020), pp. 144-156. [10.1016/j.omtn.2019.11.005]

AAV-miR-204 Protects from Retinal Degeneration by Attenuation of Microglia Activation and Photoreceptor Cell Death

Casarosa S.;
2020-01-01

Abstract

Inherited retinal diseases (IRDs) represent a frequent cause of genetic blindness. Their high genetic heterogeneity hinders the application of gene-specific therapies to the vast majority of patients. We recently demonstrated that the microRNA miR-204 is essential for retinal function, although the underlying molecular mechanisms remain poorly understood. Here, we investigated the therapeutic potential of miR-204 in IRDs. We subretinally delivered an adeno-associated viral (AAV) vector carrying the miR-204 precursor to two genetically different IRD mouse models. The administration of AAV-miR-204 preserved retinal function in a mouse model for a dominant form of retinitis pigmentosa (RHO-P347S). This was associated with a reduction of apoptotic photoreceptor cells and with a better preservation of photoreceptor marker expression. Transcriptome analysis showed that miR-204 shifts expression profiles of transgenic retinas toward those of healthy retinas by the downregulation of microglia activation and photoreceptor cell death. Delivery of miR-204 exerted neuroprotective effects also in a mouse model of Leber congenital amaurosis, due to mutations of the Aipl1 gene. Our study highlights the mutation-independent therapeutic potential of AAV-miR204 in slowing down retinal degeneration in IRDs and unveils the previously unreported role of this miRNA in attenuating microglia activation and photoreceptor cell death.
2020
Karali, M.; Guadagnino, I.; Marrocco, E.; De Cegli, R.; Carissimo, A.; Pizzo, M.; Casarosa, S.; Conte, I.; Surace, E. M.; Banfi, S.
AAV-miR-204 Protects from Retinal Degeneration by Attenuation of Microglia Activation and Photoreceptor Cell Death / Karali, M.; Guadagnino, I.; Marrocco, E.; De Cegli, R.; Carissimo, A.; Pizzo, M.; Casarosa, S.; Conte, I.; Surace, E. M.; Banfi, S.. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - STAMPA. - 19:(2020), pp. 144-156. [10.1016/j.omtn.2019.11.005]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/249530
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