An HIV drug from GSK or ones like it could have new therapeutic potential against neurodegenerative disease, findings in mice suggest.
In a report published April 26 in Neuron, scientists from the University of Cambridge described how they established a link between microglia and autophagy in the etiology of dementia and Huntington’s disease. They also showed that the HIV drug maraviroc, sold in the U.S. by GSK as Selzentry, reduced levels of key misfolded proteins in mouse models of those conditions. It also improved cognition in mice with dementia.
“We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted, potentially even with an existing, safe treatment,” senior author David Rubinsztein, Ph.D. said in a press release. “Maraviroc may not itself turn out to be the magic bullet, but it shows a possible way forward.”
To understand the findings, it helps to know a bit about autophagy and microglia. Autophagy is a cell’s waste management system, a set of processes by which damaged organelles, dysfunctional proteins and other forms of “trash” are broken down and discarded. At the end of autophagic pathways are intracellular organelles called lysosomes, which contain enzymes that break down cell debris.
Meanwhile, microglia are the central nervous system’s resident immune cells. They march around the brain and spinal cord monitoring for changes in homeostasis, responding to damage by orchestrating the release of inflammatory cytokines or anti-inflammatory molecules depending on what they encounter. That includes misfolded huntingtin and tau proteins, found in Huntington’s disease and several forms of dementia, respectively.
Scientists have noted both beneficial and detrimental links between microglia and autophagy in the context of neurodegenerative disease. On one hand, there’s evidence that microglia carry out autophagic processes of their own when they encounter the beta-amyloid plaques found in Alzheimer’s disease. But on the other, chronic microglia activation also seems to inhibit lysosome-driven autophagy that would otherwise clear out misfolded proteins.
Exactly how microglia activation inhibits autophagy has been a mystery to researchers—until now. In a series of cell experiments, Rubinsztein’s lab showed that microglia-driven cytokine release activates a receptor on the surface of neurons. Binding to this receptor called CCR5 turns on pathways that ultimately inhibit autophagy. Abnormal proteins build up as a result, permanently damaging cells.
Similar experiments in mouse models of dementia and Huntington’s disease—a progressive, inherited condition marked by an abnormal buildup of the huntingtin protein—showed a positive correlation between microglial activation, CCR5 levels and pathological protein aggregation. But in mouse models of the conditions that either didn’t have the gene for the CCR5 receptor or where CCR5 had been depleted, the researchers saw lower levels of abnormal proteins. They also found that the mice with Huntington’s disease that had been depleted of CCR5 had less severe tremors than controls and that the CCR5 knockout mice with dementia had better cognitive function than their wildtype counterparts.
To see if they could induce the same effect with a drug, the researchers turned to maraviroc. The CCR5 receptor is a co-receptor for HIV, meaning that it serves as a second binding site for the virus. Maraviroc works by blocking the CCR5 receptor, preventing HIV from latching on. The scientists reasoned that inhibiting the CCR5 receptor with maraviroc could lessen the impact of microglial activation on autophagy, allowing the abnormal proteins to be cleared more effectively.
First, they treated mice with Huntington’s disease with daily injections of maraviroc for four weeks. While they didn’t assess disease symptoms—the mice were 8 weeks old when the experiment started, and symptoms of Huntington’s usually present around 12 weeks in the models—they did find that the levels of huntingtin protein aggregates were lower in treated mice than in controls.
The same was true in the dementia models. Following the same protocol, the researchers showed that mice with dementia who were treated with maraviroc had lower levels of the abnormal protein tau in their brain than untreated models. They also outperformed them in a memory test, suggesting the drug had successfully curbed their symptoms.
This isn’t the first time a drug has been repurposed for neurodegenerative disease. Novartis’ blood cancer drug nilotinib, marketed as Tasigna, has been in clinical trials for dementia since 2015, and at one point was also being investigated for efficacy against Huntington’s. McLean, Virginia-based KeifeRx is currently recruiting for a study of the drug in patients with early-stage Alzheimer’s.