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Inherited retinal dystrophies (IRDs) are a large group of genetic diseases that lead to retinal degeneration and represent a major cause of vision impairment or blindness. The high genetic heterogeneity of IRDs hinders a broad application of gene-specific therapies. There is an unmet need for therapies that can target common pathological mechanisms, regardless of the genetic cause. MicroRNAs (miRNAs) are important players in retinal biology and my group has demonstrated that miR-204 has a pathogenic role in human IRDs. Due to their pleiotropic actions, miRNAs represent promising therapeutic tools. On this basis, I hypothesized that the modulation of miR-204 levels, as well as other miRNAs, could represent a valid approach to tackle retinal degeneration. The first part of my thesis elucidates the potential of miR-204 administration as a therapeutic approach for IRDs. I found that administration of miR-204 by an adeno-associated viral (AAV) vector at patient-relevant stages of disease progression led to a long-term preservation of retinal function in a mouse model for a dominant form of Retinitis Pigmentosa (RP). Interestingly, transcriptome analysis revealed that miR-204 effect is mediated by dampening pathological processes shared by different IRDs (e.g. innate immune response). The second part of my work was focused on identifying additional miRNAs that can exert a protective action in IRDs in a gene-independent manner. Using a High Content Screening (HCS) approach I tested 560 miRNAs in a model of oxidative stress-induced retinal degeneration, the light-damage in cone-like cells (661W). As a result, I found that miR-429 significantly preserved 661W viability during photo-stress. Further analysis revealed that miR-429 overexpression increases the activated form of the pro-survival AMP-activated protein kinase (AMPK), recently demonstrated to be protective during retinal degeneration. Overall, the results of this thesis indicate that modulation of miRNAs can be a pr

Inherited retinal dystrophies (IRDs) are a large group of genetic diseases that lead to retinal degeneration and represent a major cause of vision impairment or blindness. The high genetic heterogeneity of IRDs hinders a broad application of gene-specific therapies. There is an unmet need for therapies that can target common pathological mechanisms, regardless of the genetic cause. MicroRNAs (miRNAs) are important players in retinal biology and my group has demonstrated that miR-204 has a pathogenic role in human IRDs. Due to their pleiotropic actions, miRNAs represent promising therapeutic tools. On this basis, I hypothesized that the modulation of miR-204 levels, as well as other miRNAs, could represent a valid approach to tackle retinal degeneration. The first part of my thesis elucidates the potential of miR-204 administration as a therapeutic approach for IRDs. I found that administration of miR-204 by an adeno-associated viral (AAV) vector at patient-relevant stages of disease progression led to a long-term preservation of retinal function in a mouse model for a dominant form of Retinitis Pigmentosa (RP). Interestingly, transcriptome analysis revealed that miR-204 effect is mediated by dampening pathological processes shared by different IRDs (e.g. innate immune response). The second part of my work was focused on identifying additional miRNAs that can exert a protective action in IRDs in a gene-independent manner. Using a High Content Screening (HCS) approach I tested 560 miRNAs in a model of oxidative stress-induced retinal degeneration, the light-damage in cone-like cells (661W). As a result, I found that miR-429 significantly preserved 661W viability during photo-stress. Further analysis revealed that miR-429 overexpression increases the activated form of the pro-survival AMP-activated protein kinase (AMPK), recently demonstrated to be protective during retinal degeneration. Overall, the results of this thesis indicate that modulation of miRNAs can be a pr