Alu cDNA Strongly Implicated in Geographic Atrophy

Article: DNA in Cell Cytoplasm Implicated in Age-Related Blindness
Source: The Scientist
Published: September 29, 2021
Article: Toxic DNA Buildup in Eye May Drive Macular Degeneration
Source: University of Virginia Medicine
Published: September 30, 2021
Article: Inhibiting Inflammation Blocks Retinal Death in Animal Models of an Untreatable Blindness
Source: Genetic Engineering & Biotechnology News
Published: September 30, 2021 

Retina cross-section: photoreceptors at top (green) with RPE above, not pictured

Geographic atrophy (GA) is often considered an advanced form of nonexudative age-related macular degeneration (dry AMD), and although the etiology of centrifugal (outward) spread of the disease from the midperiphery of the retina to the central retina is well studied, the underlying mechanism of pathophysiology is poorly understood. New research strongly suggests that toxic levels Alu complementary DNA (cDNA) at the active leading edge of the "geography of atrophy," confirmed for the first time in human eye specimens (n=20), is responsible for the expansion of the lesion that gradually leads to vision loss. The Alu cDNA, a cytoplasmic self-priming retrotransposon reverse-transcribed from noncoding RNA, triggers activation of the inflammasome, a multiprotein complex of the innate immune system found in the cell cytosol that triggers inflammation and ultimately leads to cytotoxicity and damage to the retinal pigmented epithelium (RPE) that supports retinal health and function. The accumulation of Alu RNA repeats in turn is due to age-related decline in an enzyme called DICER1. In terms of mechanism, the Alu RNA leads to Alu cDNA formation via L1 reverse transcriptase. The Alu cDNA engages a DNA sensing enzyme called cGAS to trigger the escape of mitochondrial DNA into the cell’s cytosol, which in turn amplifies cGAS in a feedback loop (due to the presence of two DNA populations) that triggers the inflammasome (specifically the NLRP3 component), ultimately resulting in RPE and retinal degeneration.

In an earlier obervational study, senior author Jayakrishna Ambati, MD, demonstrated that FDA-approved nucleoside reverse transcriptase inhibitors (NRTIs) are associated with reduced risk of developing advanced dry macular degeneration in people. His company Inflammasome Therapeutics is working on alkylated derivatives called Kamuvudines that are safer (less toxic) in that they inhibit inflammasome activation but not the reverse transcription of Alu RNA. When asked why he chose to target the endpoint of the inflammasome rather than upstream points in this pathway, such as the complement pathway, Ambati replied, “Alu cDNA causes RPE degeneration via the DNA sensor cGAS. However, there are other toxic substances such as amyloid-beta, complement, and iron, which also play a role in Geographic Atrophy. Therefore, we believe that Kamuvudines which block inflammasome activation induced by these various toxic substances are a rational therapeutic approach to block this multipronged assault.” Given the strong data related to NRTIs, Ambati's team plans on starting clinical trials in 2022. He states, "[T]he planned clinical trial will enroll patients who have early stages of Geographic Atrophy, not involving the center of the retina. The goal of Kamuvudine treatment is to stop or reduce the rate of progression of the disease. This has been the typical strategy of most clinical trials to date with other drug candidates." Although limited by pre-clinical studies, Jayakrishna Ambati's meticulous research methodology and astounding findings are a major clinical advance for a devastating disease that thus far as no treatment.

My rating of this study: ⭐⭐⭐⭐⭐

Fukuda S, Narendran S, Varshney A, et al. "Alu  complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity." Science Advances.  7(40). 29 September 2021. https://doi.org/10.1126/sciadv.abj3658