Erik Roberson, M.D., Ph.D.Researchers at UAB have discovered a surprising modification that could make an emerging therapy for frontotemporal dementia (FTD) more effective, potentially helping guide the next generation of treatments for a devastating disease that currently has no cure.
The study, recently published in Science Translational Medicine, is titled “Carboxy-terminal blockade of sortilin binding enhances progranulin gene therapy in a mouse model of frontotemporal dementia.” It was directed by Erik D. Roberson, M.D., Ph.D., professor and Rebecca Gale–Heersink Endowed Chair in the UAB Department of Neurology and led by two UAB trainees, M.D./Ph.D. student Shreya Kashyap, M.D., Ph.D., and postdoctoral fellow Stephanie Fox, Ph.D.
FTD is a progressive brain disorder that often develops in people in their 50s and 60s, causing profound changes in personality, behavior, and language. Some forms of the disease are caused by mutations in the GRN gene, which reduce levels of a critical protein called progranulin. When progranulin levels fall, the brain's cellular recycling system, known as the lysosome, begins to malfunction, ultimately contributing to neurodegeneration.
Shreya Kashyap, M.D., Ph.D.For years, Roberson's laboratory has explored gene therapy to restore progranulin levels in the brain. Earlier studies from the group helped demonstrate that delivering the progranulin gene could improve disease-related abnormalities in mouse models, work that contributed to the launch of several clinical trials; however, a question remained.
“When researchers try to make a gene therapy work better, they usually focus on the delivery side: which virus to use to carry the gene, how much to give, or where in the brain to place it,” Roberson said. “We wanted to ask a different question: does the design of the cargo itself, the actual protein being delivered, matter just as much?”
In those earlier experiments, researchers attached a small molecular tag to progranulin to track where the protein traveled in the brain.
Stephanie Fox, Ph.D.“We later realized that the tag happened to sit right where progranulin attaches to a receptor called sortilin, and it blocked that interaction almost by accident,” Roberson said. “So, we had a question hanging over our original work: how much of our therapy’s success came from the progranulin itself, and how much came from that blockade of sortilin?”
To find out, the researchers created two versions of the same gene therapy. One version allowed progranulin to bind sortilin normally. The other blocked that interaction. They then tested both approaches head-to-head in mice lacking progranulin.
“The difference was substantial,” Roberson said. “When progranulin could still bind sortilin normally, the therapy produced less protein, and that protein didn't spread as far through the brain. It also fell short on the outcomes that matter most: it failed to calm inflamed immune cells in the brain, failed to normalize behavior, and failed to lower a blood marker of brain damage. Blocking the sortilin interaction fixed all of that.”
When sortilin binding was blocked, the therapy produced higher levels of progranulin and enabled the protein to spread farther throughout the brain. The modified therapy also reduced harmful brain inflammation, corrected disease-related lipid abnormalities, restored normal patterns of behavior identified through advanced machine-learning analysis, and lowered blood levels of neurofilament light chain, a biomarker linked to nerve cell damage and disease progression. In contrast, the version that retained normal sortilin binding showed more limited benefits in several of these key measures.
One of the most important findings involved microglia, the brain's immune cells. The modified therapy was particularly effective at reducing microglial dysfunction and inflammation, changes increasingly believed to contribute to neurodegeneration in FTD.
The study ultimately suggests that the design of the therapeutic protein itself may be just as important as the viral delivery system used to transport it.
“In short, the twist in this story is that a feature we originally added just to track the protein turned out to be a key ingredient in why the therapy worked as well as it did,” Roberson said.
The discovery could have important implications for the future of FTD treatment. Several progranulin gene therapies are already being tested in patients, and the UAB team's findings suggest that future versions may work better if they are engineered to avoid binding to sortilin.
Beyond gene therapy, the work also connects with ongoing efforts to develop drugs and antibodies that target sortilin. According to Roberson, the findings indicate that these approaches may complement one another rather than compete.
“Our findings suggest these strategies and gene therapy aren't competing with each other,” Roberson said. “They're addressing the same underlying vulnerability, and there may be real value in combining them, or in designing next-generation gene therapies that block the sortilin interaction.”
In addition to researchers from the UAB Killion Center for Neurodegeneration and Experimental Therapeutics and the UAB Frances Gorrie Alzheimer’s Disease Center, additional authors on the study represent labs at the Gladstone Institute of Neurological Disease, University of California, San Francisco, Memorial Sloan Kettering Cancer Center, and Howard Hughes Medical Institute.
“That collaboration is what let us ask a fairly simple question,” Roberson said, “‘Does this minor tweak to progranulin make the gene therapy better?’ and answer it rigorously in a way that we hope will inform how future progranulin gene therapies are designed and improve the care of FTD patients.”