New Huntington's disease treatment prevents protein aggregation in mice

Designer polymer disrupts protein interactions to maintain cell health in mouse study

Under research published in scientific progress, Scientists at Northwestern University and Case Western Reserve University have developed the first polymer-based treatment for Huntington's disease, an incurable and debilitating disease that causes the destruction of nerve cells in the brain.

People with Huntington's disease have a genetic mutation that causes proteins to misfold and clump together in the brain. These clumps interfere with cell function and ultimately lead to cell death. As the disease progresses, patients lose the ability to speak, walk, swallow, and concentrate. Most patients die within 10 to 20 years after symptoms first appear.

The new treatment utilizes peptide brush polymers that act as a shield to prevent proteins from binding to each other. In studies using mice, this treatment was successful in rescuing neurons and reversing symptoms. No significant side effects were observed in the treated mice, confirming that the treatment was non-toxic and well-tolerated.

The treatment requires further testing, but researchers believe it could one day be given as a once-weekly injection to delay the onset of the disease or reduce symptoms in patients with the genetic mutation. I imagine there is.

“Huntington's disease is a terrifying, insidious disease,” Northwestern University said. Dr. Nathan Gianneschiled the development of polymer therapeutics. “If you have this genetic mutation, you will get Huntington's disease. It is inevitable. There is no way out. There is no real treatment to stop or reverse the disease, and there is no cure.” really needs help. So we started thinking of new ways to deal with this disease. Misfolded proteins interact and aggregate. We counteract those interactions. We have developed a polymer that can.

Gianneschi is the Jacob and Rosalyn Cohn Professor of Chemistry at Northwestern University. Weinberg College of Arts and Sciences Professor of Materials Science Engineering and Biomedical Engineering at Northwestern University McCormick School of Engineering similarly pharmacology at Northwestern University Feinberg School of Medicine. he is also a member of International Institute of Nanotechnology. Gianneschi co-led the study with Dr. Hsin Chi, co-director of the Center for Mitochondrial Research and Treatment at Case Western Reserve University and the Janet M. Silver and Joseph S. Silver Professor of Neuroscience.

promising peptides

The new study is based on Previous research from Qi's lab At Case Western Reserve. In 2016, Qi and his team identified a protein (valosin-containing protein, or VCP) that abnormally binds to mutant Huntington proteins and causes protein aggregation. These aggregates accumulate within the cell's mitochondria, organelles that produce the energy needed to fuel the cell's biochemical reactions. Without functioning mitochondria, cells become dysfunctional and then self-destruct.

As part of that research, Qi also discovered a naturally occurring peptide that disrupts the interaction between VCP and mutant huntingtin proteins. In cells exposed to the peptide, both the VCP protein and the mutant huntingtin protein bound to the peptide but not to each other.

“Qi's team has identified a peptide that comes from the mutant protein itself and essentially controls the interface between proteins,” Gianneschi said. “The peptide inhibited mitochondrial death, so we found it promising.”

pulls proteins apart like velcro

However, the peptide itself had some limitations. Because peptides are easily broken down by enzymes, they have a short lifespan in the body and are often difficult to effectively enter cells. For a peptide to inhibit Huntington's disease, it must cross the blood-brain barrier in sufficient quantities to prevent large-scale protein aggregation.

“This peptide occupies a very small area at the protein interface,” Gianneschi said. “Proteins stick to each other like Velcro. In this analogy, one protein has hooks and the other has loops. The peptide itself can be pulled apart one hook and loop at a time to create a patch of Velcro. It's like trying to put it back on. By the time I got to the bottom of the patch, the top had already undone and was sealed again, so I needed something big enough to mess with the whole interface. .”

To overcome these obstacles, Gianneschi and his team developed biocompatible polymers that display multiple copies of the active peptide. The new structure has a polymer backbone with peptides attached like branches. This structure not only protects the peptide from destructive enzymes, but also helps the peptide cross the blood-brain barrier and enter cells.

Experimental results

In laboratory experiments, Gianneschi and his team injected a protein-like polymer into a mouse model of Huntington's disease. This polymer remained in the body 2,000 times longer than traditional peptides. In biochemical and neuropathological tests, researchers found that the treatment prevented mitochondrial fragmentation and maintained brain cell health. Mice with Huntington's disease lived longer and behaved more like normal mice, Gianneschi said.

“In one study, mice were tested in field trials,” Gianneschi said. “In animals with Huntington's disease, as the disease progresses, they stay along the edges of the box. Normal animals move back and forth to explore space. Animals treated for Huntington's disease do the same. It's very convincing to see animals behaving more normally.”

Next, Gianneschi plans to continue optimizing the polymer and consider its use in other neurodegenerative diseases.

“My childhood friend was diagnosed with Huntington's disease at the age of 18 through genetic testing,” Gianneschi said. “He is currently in a nursing home as he requires full-time care 24 hours a day. I remain highly motivated both personally and scientifically to continue on this path.”

This research was supported by National Institutes of Health International Nanotechnology Interdisciplinary Scientific and Medical Research Institute grants (award numbers 1F31AG076334, R01AG065240, R01NS115903, R01AG076051, and RF1AG074346).