Researchers at Northwestern and Case Western Reserve universities have developed a pioneering polymer-based therapeutic that shows promise in reversing Huntington’s disease symptoms in mice, potentially transforming treatment for the incurable illness.
In a significant breakthrough, scientists from Northwestern University and Case Western Reserve University have developed the first polymer-based therapeutic for Huntington’s disease, a debilitating and fatal neurological disorder. This advancement offers new hope for individuals suffering from the condition, which currently has no cure.
Huntington’s disease is caused by a genetic mutation that leads to the misfolding and aggregation of proteins in the brain. These toxic clumps damage nerve cells, leading to the progressive loss of motor skills and cognitive functions. Most patients succumb to the disease within 10 to 20 years after symptoms appear.
The newly developed treatment employs peptide-brush polymers that act as a shield, preventing the harmful proteins from clumping together. In preclinical trials with mice, this innovative approach successfully protected neurons, reversing disease symptoms without significant side effects.
The researchers anticipate that further testing could pave the way for this therapy to be administered as a once-weekly injection, potentially delaying disease onset or mitigating symptoms in humans.
“Huntington’s is a horrific, insidious disease,” Nathan Gianneschi, a professor at Northwestern who led the research, said in a news release. “If you have this genetic mutation, you will get Huntington’s disease. It’s unavoidable; there’s no way out. There is no real treatment for stopping or reversing the disease, and there is no cure. These patients really need help. So, we started thinking about a new way to address this disease. The misfolded proteins interact and aggregate. We’ve developed a polymer that can fight those interactions.”
Gianneschi collaborated with Xin Qi, a professor at Case Western Reserve. Qi’s earlier research identified a naturally occurring peptide that could prevent the clumping of proteins. However, peptides alone are quickly degraded by natural processes in the body, making them less effective.
“The peptide has a very small footprint with respect to the protein interfaces,” Gianneschi added. “The proteins stick to each other like Velcro. In this analogy, one protein has hooks and the other has loops. The peptide, on its own, is like trying to undo a patch of Velcro by pulling apart one hook and loop at a time. By the time you get to the bottom of the patch, the top has already come back together and resealed. We needed something big enough to disrupt the entire interface.”
To enhance the efficacy and stability of the peptide, the team attached it to a biocompatible polymer backbone. This structure not only shields the peptide from enzymatic degradation but also improves its ability to cross the blood-brain barrier and reach the target sites in the brain.
In experiments, the novel polymer-like structure remained in the body 2,000 times longer than traditional peptides. The researchers observed notable preservation of neuron health and extended lifespan in mice models of Huntington’s disease. Behavior tests also showed that treated mice exhibited more normal behaviors compared to untreated ones, highlighting the potential of this therapy to improve quality of life.
“In one study, the mice are examined in an open field test,” added Gianneschi. “In the animals with Huntington’s, as the disease progresses, they stay along the edges of the box. Whereas normal animals cross back and forth to explore the space. The treated animals with Huntington’s disease started to do the same thing. It’s quite compelling when you see animals behave more normally than they would otherwise.”
The research team is committed to further refining the polymer for potential applications in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
“My childhood friend was diagnosed with Huntington’s at age 18 through a genetic test,” Gianneschi said. “He’s now in an assisted living facility because he needs 24-hour, full-time care. I remain highly motivated — both personally and scientifically — to continue traveling down the path.”
The promising study, published in the journal Science Advances, heralds a new era in the fight against Huntington’s disease and offers a glimmer of hope to those afflicted by it.