Dicer1 Gene Therapy as a Treatment for Age-Related Macular Degeneration

Age-related macular degeneration is a common form of vision loss. It begins as a dry form, and progresses to a wet form as blood vessels inappropriately grow into damaged retinal tissue. Researchers have identified downregulation of Dicer1 as a factor in the progression of the condition, and here demonstrate that a gene therapy to increase expression of Dicer1 may form the basis for a therapy targeting both dry and wet stages of macular degeneration. That increased expression acts to block a significant cause of inflammation and cell death in retinal tissue.

Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown.

Deficiency of DICER1, an RNase that processes double-stranded and self-complementary RNAs including a majority of premature micro-RNAs (miRNAs) into their bioactive forms, is among the inciting molecular events implicated in atrophic AMD. DICER1 deficiency is implicated in RPE cell death in atrophic AMD due to accumulation of unprocessed Alu RNAs, which results in noncanonical activation of the NLRP3 inflammasome, an innate immune pathway resulting in RPE death.

We report that genetic suppression of Dicer1 in three independent mouse models manifests in the eye as focal RPE atrophy and aberrant choroidal and retinal neovascularization, and that DICER1 expression is reduced in a mouse model of spontaneous choroidal neovascular (CNV) lesions. Furthermore, we report that AAV-enforced expression of a DICER1 construct reduces spontaneous CNV in mice. In addition to expanding upon prior studies of DICER1 loss in atrophic AMD, these findings identify maintenance of outer retinal avascularity as another critical function of DICER1 in maintaining retinal homeostasis. This study also suggests that restoring DICER1 expression in the retina could itself be a viable therapeutic target for the treatment of AMD.

Link: https://doi.org/10.1073/pnas.1909761117

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