Anasagasti Ander, Lara-López Araceli, Milla-Navarro Santiago, Escudero-Arrarás Leire, Rodríguez-Hidalgo María, Zabaleta Nerea, González Aseguinolaza Gloria, de la Villa Pedro, Ruiz-Ederra Javier
Sensorial Neurodegeneration Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
Viralgen Vector Core, 20009 San Sebastián, Spain.
Pharmaceutics. 2020 Sep 24;12(10):913. doi: 10.3390/pharmaceutics12100913.
Inherited retinal dystrophies (IRDs) are a group of rare retinal conditions, including retinitis pigmentosa (RP), caused by monogenic mutations in 1 out of more than 250 genes. Despite recent advancements in gene therapy, there is still a lack of an effective treatment for this group of retinal conditions. MicroRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that inhibit gene expression. Control of miRNAs-mediated protein expression has been described as a widely used mechanism for post-transcriptional regulation in many physiological and pathological processes in different organs, including the retina. Our main purpose was to test the hypothesis that modulation of a group of miRNAs can protect photoreceptor cells from death in the rd10 mouse model of retinitis pigmentosa. For this, we incorporated modulators of three miRNAs in adeno-associated viruses (AAVs), which were administered through sub-retinal injections. The results obtained indicate that inhibition of the miR-6937-5p slows down the visual deterioration of rd10 mice, reflected by an increased electroretinogram (ERG) wave response under scotopic conditions and significant preservation of the outer nuclear layer thickness. This work contributes to broadening our knowledge on the molecular mechanisms underlying retinitis pigmentosa and supports the development of novel therapeutic approaches for RP based on miRNA modulation.
遗传性视网膜营养不良（IRDs）是一组罕见的视网膜疾病，包括色素性视网膜炎（RP），由250多个基因中的一个发生单基因突引起。尽管基因治疗最近取得了进展，但对于这组视网膜疾病仍缺乏有效的治疗方法。微小RNA（miRNA）是一类高度保守的小非编码RNA，可抑制基因表达。在包括视网膜在内的不同器官的许多生理和病理过程中，miRNA介导的蛋白质表达调控已被描述为一种广泛使用的转录后调控机制。我们的主要目的是检验这样一个假设，即调节一组miRNA可以保护视网膜色素变性rd10小鼠模型中的光感受器细胞免于死亡。为此，我们将三种miRNA的调节剂整合到腺相关病毒（AAV）中，通过视网膜下注射进行给药。获得的结果表明，抑制miR-6937-5p可减缓rd10小鼠的视力恶化，这表现为在暗视条件下视网膜电图（ERG）波反应增加以及外核层厚度的显著保留。这项工作有助于拓宽我们对色素性视网膜炎潜在分子机制的认识，并支持基于miRNA调节的RP新型治疗方法的开发。
