Patients diagnosed with Huntington’s disease carry a genetic mutation that causes proteins to misfold, leading to aggregation in the brain. These protein clumps disrupt cellular processes and ultimately result in cell death. A novel treatment has been developed that utilizes peptide-brush polymers, which serve as a barrier against protein aggregation. Research conducted on mice has shown that this treatment can restore neurons and alleviate symptoms.
Researchers from Northwestern University and Case Western Reserve University have created the first polymer-based therapy for Huntington’s disease, a devastating and incurable condition that causes the degeneration of neurons in the brain.
Individuals with Huntington’s disease possess a genetic mutation that triggers the misfolding of proteins in the brain, resulting in their aggregation. These aggregates disrupt normal cell functions and lead to cell death. As the disease advances, patients increasingly struggle with basic functions such as speaking, walking, swallowing, and concentrating. The majority of those affected typically succumb to the illness within a decade or two after the initial symptoms emerge.
The innovative treatment centers on peptide-brush polymers, which act as a protective shield to prevent the binding of proteins. In experiments with mice, this therapy successfully revitalized neurons and reversed some symptoms. Mice receiving the treatment exhibited no major side effects, confirming the therapy’s non-toxic nature and good tolerance.
While the therapy requires additional testing, the researchers hope it may eventually be delivered as a once-weekly injection to postpone the onset of the disease or alleviate symptoms in individuals with the mutation.
The findings are set to be published on Friday (Nov. 1) in the journal Science Advances.
“Huntington’s is an atrocious and relentless disease,” stated Nathan Gianneschi of Northwestern, who spearheaded the development of the polymer therapy. “Anyone with this genetic mutation will inevitably develop Huntington’s. There’s no alternative, no stopping or reversing the illness, and no cure. These patients are in dire need of assistance. We devised a new strategy to tackle the disease. The misfolded proteins interact and clump together. We have created a polymer to combat those interactions.”
Gianneschi holds the Jacob and Rosaline Cohn Professorship in Chemistry at Northwestern’s Weinberg College of Arts and Sciences, along with positions in materials science and engineering and biomedical engineering at the McCormick School of Engineering, and pharmacology at the Feinberg School of Medicine. He is also a member of the International Institute of Nanotechnology. He co-led this research alongside Xin Qi, who is the Jeanette M. and Joseph S. Silber Professor of Brain Sciences and co-director of the Center for Mitochondrial Research and Therapeutics at Case Western Reserve University.
Promising peptide
This study builds upon previous research from Qi’s lab at Case Western Reserve, where in 2016 a protein known as valosin-containing protein (VCP) was identified as a factor that abnormally binds to the mutant form of the Huntington protein, leading to protein aggregation. These aggregates can collect in a cell’s mitochondria, the energy-producing organelles essential for cellular functions. When mitochondria fail, the cell becomes dysfunctional and may self-destruct.
During that investigation, Qi’s team also discovered a natural peptide that disrupts the interaction between VCP and the mutant Huntington protein. In cells treated with this peptide, both VCP and the mutant protein bound to the peptide instead of each other.
“Qi’s team identified a peptide derived from the mutant protein itself that regulates protein interactions,” Gianneschi explained. “This peptide reduced mitochondrial death, demonstrating its potential.”
Separating proteins like Velcro
However, the peptide alone has several drawbacks. Due to being easily degraded by enzymes, peptides have a short duration in the body and struggle to penetrate cells effectively. To be effective against Huntington’s disease, it is critical for the peptide to traverse the blood-brain barrier in sufficient quantities to prevent extensive protein aggregation.
“The peptide’s small size limits its efficacy in affecting the protein interfaces,” Gianneschi noted. “Proteins connect like Velcro. Imagine one protein having hooks and another having loops; trying to detach them using only the peptide is like attempting to separate Velcro patches one hook and loop at a time. By the time you’ve unfastened part of it, the other part reattaches. We needed something larger to disrupt the entire interface.”
To address these challenges, Gianneschi and his team engineered a biocompatible polymer that features multiple copies of the active peptide. This new composition has a polymer backbone with peptide branches. Not only does the design shield the peptides from breakdown, but it also facilitates their passage across the blood-brain barrier and into cells.
Experimental results
In laboratory tests, Gianneschi and his team injected the protein-like polymer into a mouse model of Huntington’s disease. The polymers remained in the body for 2,000 times longer than standard peptides. Biochemical and neuropathological assessments revealed that the treatment inhibited mitochondrial fragmentation, preserving brain cell health. Notably, the treated mice with Huntington’s disease showed increased lifespan and exhibited behaviors more akin to healthy mice.
“In one experiment, the mice were assessed in an open field setting,” Gianneschi reported. “Normal mice move around freely, while those with Huntington’s tend to stay around the edges. After treatment, the affected mice began to explore the area more freely, behaving much like healthy animals, which is quite striking.”
Looking ahead, Gianneschi plans to refine the polymer and explore its application in treating other neurodegenerative diseases.
“A childhood friend of mine was diagnosed with Huntington’s at 18 through genetic testing,” Gianneschi shared. “He currently resides in an assisted living facility requiring continuous care. I am deeply motivated—both personally and scientifically—to pursue this path further.”
