Blindness due to age-related dry macular degeneration (AMD) robs over 200 million people worldwide of being able to do the simplest tasks they used to take for granted, such as driving or playing with their grandkids. Currently, there is no approved treatment for AMD.

A group of drugs used to treat HIV that block DNA synthesis in the cytoplasm can be repurposed to treat an advanced form of AMD called geographic atrophy (GA), a new study suggests. The findings were published in the journal, Proceedings of the National Academy of Sciences, in an article titled, “Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.”

In addition to nuclear chromosomal DNA that we inherit from our parents and mitochondrial DNA that we inherit from our mothers, the authors have previously shown DNA is also synthesized in the cytoplasm and constitutes the key to understanding several degenerative, inflammatory diseases.

An analysis of nearly 35 million people in multiple cohorts across the United States over 20 years found that FDA-approved anti-HIV drugs that block this cytoplasmic DNA formation protected against dry macular degeneration by ~40%,” said Jayakrishna Ambati, MD, professor of ophthalmology, founding director at the Center for Advanced Vision Science at the University of Virginia, and senior author on the study.

Alu elements make up more than 10% of the human genome, and propagate by a process called “retrotransposition” which involves insertion into the genomic DNA. This is extremely rare, occurring in germlines at the rate of about 1 new Alu insertion per 20 human births, and is much rarer in other cells.

Jayakrishna Ambati, MD, professor of ophthalmology, professor & vice chair for research, ophthalmology, and founding director, Center for Advanced Vision Science, University of Virginia. (Source: Jayakrishna Ambati).

“In contrast, when Alu DNA is transcribed into Alu RNA, it can then be reverse transcribed into Alu cDNA in the cytoplasm, as we describe. This can happen if sufficient Alu RNA exists in the cytoplasm,” said Ambati. Normally, an enzyme called DICER1 keeps the abundance of Alu RNA in check. “But this is impaired in macular degeneration. Hence, Alu RNA accumulates in the retinal pigmented epithelium and becomes converted into Alu cDNA to cause degeneration.”

An enzyme called L1 reverse transcribes Alu RNA into Alu complementary DNA (cDNA) in the nucleus. The current study reports Alu is also reverse transcribed in the cytoplasm independent of retrotransposition. This occurs through self-priming and is the first evidence of human DNA synthesis occurring in the cytoplasmic compartment of the cell.

Cytoplasmic DNA can be cytotoxic. Among other things, it causes upregulation of the inflammasome complex associated with the “slow burning types of inflammation” resulting in diseases such as gout, Alzheimer’s disease, type-2 diabetes, and AMD.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been reported to be beneficial in preventing cytoplasmic DNA synthesis. “The problem with NRTIs though, is that they are all somewhat toxic,” said Paul Ashton, PhD, president and CEO of Inflammasome Therapeutics, a company founded by Ashton and Ambati, to develop therapies for prevalent degenerative diseases.

“NRTIs are toxic because they get phosphorylated in the active form which also messes up mitochondrial DNA. By preventing the phosphorylation you can make a derivative that has no activity against HIV at all but retains the same anti-inflammasome activity. Those are the compounds called Kamuvudines that we’re trying to develop now,” said Ashton.

“The present study provides the missing link between animals and humans. The authors analyzed insurance claims from databases covering more than 100 million Americans, so the data are extraordinarily robust. Importantly, the study indicates the type of response that we can expect from Kamuvudines and de-risks our planned clinical program. We know Kamuvudines and NRTIs have the same effect on inflammasome activation. We know they are both highly effective in animal models of AMD; and now we know NRTIs can prevent AMD in humans. We hope to demonstrate as we move into the clinic this year that Kamuvudines work in people,” said Ashton.

“We believe Kamuvudines may be effective against a large number of prevalent degenerative diseases involving inflammasome activation such as multiple sclerosis, Alzheimer’s, and type 2 diabetes,” said Ambati.

An earlier report from Ambati’s team in Nature Communications showed that the use of NRTIs is associated with a 30% reduced risk of developing type 2 diabetes. The earlier studies on Kamuvudines helps the team estimate the efficacy, which is an advantage to the repurposing approach. Backed by the robust preclinical data published in this PNAS report, “we’re hoping to get to clinical trials within a year,” said Ashton.

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