Doctor Jayakrishna Ambati, founding director of the University School of Medicine Center for Advanced Vision Science and School of Medicine ophthalmology professor, and his team discovered this year that HIV drugs may be a way to slow the global rise in the number of Alzheimer’s disease cases. Based on this finding, Ambati and his research team have begun work on a new drug called K9 which could treat and prevent Alzheimer’s.
Alzheimer’s disease is a progressive neurodegenerative disorder that begins with the buildup of protein in the brain and eventually causes the brain to shrink from cell death, commonly resulting in memory loss and language production difficulty. The Fisher Center for Alzheimer’s expects the rate of the disorder to increase from approximately five million currently diagnosed patients to 14 million by 2050 — scientists say this rise appears to be tied to the aging United States population.
There is currently no cure or clear method of prevention for Alzheimer’s, and researchers do not yet understand exactly what causes the disease. Some medications which can slow the onset of memory symptoms have been approved for people in the early stages of the disease, including Lecanemab and Donanemab. While these two drugs do allow people with Alzheimer’s more time to participate in daily, independent life, they ultimately cannot prevent or reverse the onset of the disease.
Ambati and his research team have worked to study a class of antiviral HIV drugs called nucleoside reverse transcriptase inhibitors, which work by blocking HIV from multiplying in the body. Ambati said his team discovered roughly 10 years ago that NRTIs can also block inflammasome activation — a key driver of many chronic diseases, including Alzheimer’s.
Ambati said their prior discovery that NRTIs can block inflammasomes sparked the research for their most recent finding that NRTIs could slow Alzheimer’s rates. Inflammasomes cause cell death in response to toxins, damaging neurons and leading to the symptoms seen in patients with Alzheimer’s disease.
“Since that initial discovery [that NRTIs block inflammasomes], we, as well as research groups [around the world], have identified that inflammasome activation is very critical in many diseases,” Ambati said.
The team analyzed two large data sets of HIV or Hepatitis B patients taking NRTIs, over the age of 50 and not already diagnosed with Alzheimer’s, to identify any affiliation with a reduction in Alzheimer’s development compared with those not taking NRTIs.
“We thought, ‘why [not] look at health insurance databases?’” Ambati said. “That’s a very rich repository of human data that you can go back and collect and analyze to see whether people who are taking NRTIs have a reduced risk of disease A or disease B or disease C.”
The first dataset Ambati and his team analyzed was a set of 24 years of data from the United States Veterans Health Administration Database which houses medical data of U.S. veterans being supported by the U.S. Department of Veterans Affairs and is primarily made up of men. Ambati and his team wrote in their research paper, published May 8, that this dataset had 72,193 patients who met the research criteria and analyzing data of those patients revealed a 6 percent annual reduction in Alzheimer’s development risk for each year they took NRTIs.
The second dataset the research team analyzed along with the first was 14 years of data from MarketScan — a vast database of employer-based healthcare insured patients in America. This dataset included 199,005 patients who met the study criteria and had a more even gender distribution. The researchers found a 13 percent annual decrease in Alzheimer’s development risk for each year the patient took NRTIs among this group.
Ambati said that while the first dataset is made up mostly of men, the races and ethnicities of the patients were more diverse than in the second dataset and gave the research team 24 years of data to work with rather than 14.
“Each [database] has its own strengths and weaknesses, but the fact that you find very similar results in both — which are very different populations — increases the confidence in the overall result being not sensitive to those changes,” Ambati said.
Though both datasets supported the finding that NRTIs can help reduce Alzheimer’s rates, Ambati said NRTIs can have adverse side effects because of their antiviral properties — these side effects include a reduction in patients’ energy levels.
To combat this, Ambati and his team have developed a new drug called K9 which directly blocks inflammasomes without any antiviral effects. Ambati said this can be a safer way to reach the same prevention of Alzheimer’s and other chronic diseases because it does not have the toxicity of NRTIs which could be especially dangerous to the elderly population.
“[NRTI] is really not the ideal drug to take if you want to stop the development or progression of Alzheimer's or any other kind of chronic disease,” Ambati said. “... So what we did is we created a modified version of these NRTIs, which we call K9, which no longer blocks the viral effects, but still blocks inflammasome effects, and as a result, it doesn't affect our mitochondrial health, and so it doesn't have that toxicity.”
Ambati noted K9 is already proving successful and is currently in two human clinical trials for eye disease, as blocking inflammasomes is important for slowing the inflammation that causes cell death in the retina. For Alzheimer’s disease specifically, he said K9 would be proven successful through clinical trials if it succeeds through two groups.
The first would be a prevention trial with a large group of elderly people predisposed to Alzheimer’s through family history or a genetic mutation, to analyze rates of Alzheimer’s prevention through the number of people who do not develop the disease while taking K9. The second group would be analyzed to view if K9 is successful at treating Alzheimer’s symptoms in patients who already have the disease. Ambati noted success of reversing symptoms has already been seen in animal test groups.
“We actually have data from animal models showing that the K9 drug actually reverses the cognitive deficits that you see in Alzheimer's Disease spectacularly,” Ambati said. “We think it can actually be used in a trial in people who already have Alzheimer's disease to slow down their progression or perhaps even reverse their cognitive deficits.”
Moving forward, Ambati hopes that the new K9 drug can be used in these possible clinical trials specifically focused on Alzheimer’s treatment and prevention.
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