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

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.

Targeting miR-181a/b in retinitis pigmentosa: implications for disease progression and therapy

“…Earlier studies showed that double knockout mice for miR-181a/b-1 and miR-181a/b-2 had a decreased body size and lower survival rate, indicating that miR-181a/b plays a crucial role in regulating vital pathways in vivo [ 49 ]. Our study focuses on the ablation of miR-181a/b-1, which has previously been shown to rescue neurodegenerative disorders, including RP [ 18 , 36 ]. Our model still expresses miR-181a/b-2, generating a downregulation of miR-181a/b instead of knockout (Fig.…”

“…Dysregulation of miRs has been observed in retinal disorder, which may represent compensatory survival mechanisms or contribute to disease progression [ 14 – 17 ]. Importantly, miR modulation has demonstrated beneficial effects for RP treatment [ 18 – 20 ].…”

“…The downregulation of miR-181a/b has shown therapeutic benefits in neurodegenerative disorders, including RP caused by mutations in the Rhodopsin ( Rho ) and Phosphodiesterase 6β ( Pde6β ) genes [ 18 , 36 ]. The use of an adeno-associated viral vector (AAV) carrying a miR-181a/b complementary sequence, referred to as a “sponge”, improved mitochondrial morphology and function in PR cells.…”

“…This data suggests that simultaneous downregulation of miR-181a/b in multiple cell types within the retina is crucial for achieving optimal therapeutic outcomes. Surprisingly, no therapeutic benefits were observed when an RPE-specific promoter was utilized [ 18 ]. However, in vivo delivery of episomal vectors to the mouse RPE using a ubiquitous promoter such as cytomegalovirus (CMV) resulted in higher transgene expression than RPE-specific promoters [ 37 ].…”

Artificial intelligence utility for drug development: ChatGPT and beyond

“…Here, we examined the capacity, efficiency, and value of ChatGPT to provide information relevant to drug development. We chose to ask mostly questions requesting information relevant to the development of novel antidepressant drugs, including tentative nucleotide‐based therapeutics, a topic of wide interest (Jordheim et al, 2013; Kamel et al, 2023; Li et al, 2022; Müller et al, 2017); as well as microRNA therapeutics (Carrella et al, 2022; Duan et al, 2023; Jia et al, 2023). We are aware that the examples of our questions and the ChatGPT replies shown in the Supporting Information: File represent a tiny fraction of the multifaceted aspects of drug development, or the IT capacities of ChatGPT.…”