CHARLOTTESVILLE — University of Virginia researchers say a group of HIV-preventing drugs could prevent age-related dry macular degeneration, the most common cause of blindness, and they hope to begin clinical trials later this year.
About 10 million Americans are affected by the disease.
Working with others across the country and internationally, the UVa team found the possible connection even as it made a breakthrough discovery that a form of DNA, called Alu, was replicating in the cytoplasm of cells.
Previously, it was believed that DNA was created only in a cell’s mitochondria and nucleus.
The research follows on a previous discovery the team made that Alu RNA causes cell death in the retina by inciting an inflammatory response in the cells.
“We normally have mechanisms to keep these types of molecules under check, but as we age, those mechanisms begin to fail and these rogue molecules create inflammasomes. When that gets activated, cells in the retina die and macular degeneration takes place,” said Dr. Jayakrishna Ambati, director of the UVa Center for Advanced Vision Science and a professor of ophthalmology at UVa’s School of Medicine.
Inflammasomes are a normal part of a healthy human body and serve as part of the body’s defense system against bacteria and other invaders. Problems begin, however, when the body’s natural control mechanisms don’t tamp down the inflammasomes and the molecules run amok.
“We all learn that DNA we inherit from our parents is in the nucleus of cells and the DNA from our mothers is in the mitochondria, but we discovered the Alu molecule is being made in the cytoplasm, and that’s a complete change,” Ambati said.
Simplified, the process begins with Alu DNA creating Alu RNA. The RNA has the unique ability create more Alu DNA, which creates more RNA. The molecule is associated with a variety of diseases, including Type II diabetes, Alzheimer’s and multiple sclerosis.
The fact that Alu replicates its DNA much like a retrovirus led Ambati’s team to look toward drugs currently used to prevent HIV, a retrovirus. Lab tests showed the drugs could help by reducing inflammation and thwarting replication.
“They are taken as a preventative for HIV by people who do not have HIV, and the Alu molecules are very similar in the way they replicate themselves,” Ambati said. “These drugs have been in use for several decades and we know their side effects, their safety records. The older generations of the drugs are really nasty and the newer ones aren’t fun to take, either, especially for older people.”
Ambati and his team also hit the Virginia Initiative for Accelerating Drugs electronic paper trail, digging like data archaeologists through medical meta information gathered by insurance companies on some 35 million adults.
The initiative is funded by a $1 million grant from the Virginia Strategic Investment Fund and is designed to determine whether any of the existing 3,000 approved drugs in the U.S. also can be used on any of the 17,000 known diseases, especially those with no known cure.
“There are great things going on through the initiative,” Ambati said. “If we could find a drug approved for one treatment that is effective in treating or preventing another disease, that is like a present.”
The data mining showed the HIV drugs, known as nucleoside reverse transcriptase inhibitors, seemed to reduce the risk of developing the eye disease by 40%. They are focusing on a particular type of NRTI called kamuvudines.
“We now have real data that there are drugs that could be helpful in this disease,” Ambati said.
He co-founded Inflammasome Therapeutics to investigate the use of kamuvudines in age-related dry macular degeneration. The company hopes to open up clinical trials in the late summer or early fall, the pandemic permitting.
“I really think there’s something here,” Ambati said. “We hope to have the clinical trials starting and we think they are going to show that this is effective. This could make a big difference in people’s lives.”