University researchers are conducting a phase one clinical trial that will look at the potential therapeutic effect that a class of HIV drugs can have on the progression of Alzheimer’s Disease.
The 2.5 year clinical trial was funded through a $750,000 grant from the Alzheimer’s Association Part the Cloud Translational Research Funding program, which the researchers learned they would receive at the end of 2019. This initiative is a relatively new program funded by the largest private financial supporter of Alzheimer’s research in the world, said Stephen Salloway, director of neurology and the memory and aging program at Butler Hospital, Martin M. Zucker professor of psychiatry and human behavior and professor of neurology and co-principal investigator of the trial. “This is a very prestigious award, and we are very excited to have this opportunity.”
The researchers’ primary goal for this trial is to test an HIV drug called emtricitabine, sold as Emtriva, in older people with Alzheimer’s disease to ensure that the drug is safe and that patients tolerate it well, Salloway said. Their secondary goal is to look at the effect that emtricitabine has on inflammation, memory and daily function. “This is a very favorable circumstance for research since we have the drug on the shelf, and we can repurpose (it) for another disease,” Salloway said.
The study was inspired by earlier experiments conducted by John Sedivy, Hermon C. Bumpus professor of biology and professor of medical science and co-principal investigator of the current clinical trial. The prior studies found that an HIV drug, Lamivudine, could decrease inflammation in various mice tissues. Lamivudine blocks the activity of the HIV-linked reverse transcriptase enzyme, a molecular substance that allows HIV to replicate and incorporate into people’s DNA. The findings showed that retrotransposable elements, which are portions of DNA that can reinsert into other parts of a person’s genome, were likely implicated in this inflammation.
While these retrotransposable elements are normally suppressed and therefore unnoticed by the body, Sedivy’s research suggests that the aging body reacts to the activation of the retrotransposable elements and triggers a response from the immune system. This leads to “sterile inflammation.” While most types of inflammation are a response to an infection, sterile inflammation is different because, as far as doctors can tell, those experiencing it are not necessarily infected. “More recently, it is now believed that this sterile inflammation … may not be the cause, but it exacerbates diseases normally associated with old age,” Sedivy said.
Patients with Alzheimer’s disease, or other neurologic diseases, have been shown to have inflammation in the brain. “No one really knows where this neuroinflammation is coming from. Our idea is that it might be coming from these retrotransposable elements,” Sedivy added.
After discovering what may be a link between the elements and aging-affiliated diseases, Sedivy approached Salloway, who has conducted numerous Alzheimer’s studies.
The team for this project also includes University researchers and partners abroad. Rami Kantor, professor of medicine at the division of infectious diseases, HIV physician-scientist and co-director of Providence/Boston Center for AIDS Research, was approached by Sedivy, who expressed interest in the potential incorporation of HIV medications for non-HIV purposes. “My role is to follow the (study participants) clinically to make … sure (the medications) are safe.”
For this clinical trial, the researchers are focusing on emtricitabine. “While very similar to Lamivudine, (emtricitabine) has (fewer) side effects, and it is a bit more efficacious,” Kantor said. Yet, the “mechanism of action is the same.”
Emtricitabine is currently prescribed to millions of people as HIV therapy and is “very well tolerated,” Sedivy said. Still, the researchers are concerned about unanticipated side effects that these drugs may have when given to the target subjects of the study: older people and specifically older people with Alzheimer’s disease. But older people with HIV have already been using these kinds of drugs without experiencing adverse reactions exceeding those of younger patients, so “there really are no significant red flags,” Sedivy said.
Using emtricitabine and lamivudine in individuals without HIV is not an entirely novel concept. Some people who are at high risk of developing HIV have already taken lamivudine and emtricitabine as components of their treatment and have mostly tolerated the drugs, Kantor said.
The researchers are awaiting final approval from the Institutional Review Board. Afterwards, the company that produces Emtriva, Gilead Sciences Inc., will prepare and supply the drug for the research.
Following media coverage of the trial, people have expressed interest in participating in the study. The double-blind study will provide 25 participants with the active emtricitabine drug and 10 others with a placebo, which is an inactive control drug. All 35 participants will have to have early Alzheimer’s disease to qualify for the trial.
“There is the big hope and expectation, which I think everybody shares, that this will possibly be a cure for Alzheimer’s,” Sedivy said. But the phase one clinical trial that the researchers are undertaking “is the very first baby step in that direction.”