Polymer Therapy Reverses Huntington’s Symptoms

Scientists at Northwestern University and Case Western Reserve University have developed the first polymer-based therapy for Huntington’s disease. Published in Science Advances, the novel molecule prevents toxic protein clumping and shows promise in reversing symptoms in mice models.

Huntington’s disease is an incurable, fatal disorder

Huntington’s disease is a rare, inherited neurodegenerative disorder that impacts ~41,000 Americans. The genetic disease results from a mutation in the HTT gene, where an abnormal expansion of CAG nucleotide repeats triggers the production of mutant huntingtin protein. The mutated protein misfolds, which leads to toxic clumps, or aggregates, in the brain. These protein clumps accumulate within neurons and interfere with their function, causing cell death and progressive brain damage.

Symptoms of Huntington’s disease tend to start between the ages of 30 and 50, and gradually increase over 10 to 20 years as the condition progresses. Patients experience uncontrolled movement, muscle rigidity, cognitive decline and extreme changes in personality. Eventually they lose the ability to walk, talk and swallow, requiring full-time care. The disease is ultimately fatal.

Currently, there is no cure or treatment that can halt, slow or reverse the progression of Huntington’s disease. Existing therapeutic strategies focus on alleviating symptoms and improving quality of life, such as medications that manage involuntary movements and those prescribed for the psychiatric symptoms associated with the disease.

“Huntington’s is a horrific, insidious disease. 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,” said co-corresponding author Dr. Nathan Gianneschi, the Jacob and Rosaline Cohn professor of chemistry at Northwestern’s Weinberg College of Arts and Sciences and professor of materials science and engineering and biomedical engineering at Northwestern’s McCormick School of Engineering.

Identifying a naturally occurring peptide

Dr. Xin Qi, co-corresponding author and the Jeanette M. and Joseph S. Silber Professor of Brain Sciences at Case Western Reserve University, and her team discovered a protein – valosin-containing protein, or VCP – which binds abnormally to the mutant Huntingtin protein in 2016. When VCP binds to the mutant protein it causes the protein to form aggregates, which accumulate within a cell’s mitochondria. The resulting lack of functional mitochondria causes the cells to become dysfunctional and self-destruct.

Qi and the team also identified a naturally occurring peptide that disrupts the interaction between VCP and the mutant Huntingtin protein. When cells were exposed to the peptide, VCP and the mutant protein bound to the peptide, instead of each other.

“Qi’s team identified a peptide that comes from the mutant protein itself and basically controls the protein–protein interface. That peptide inhibited mitochondrial death, so it showed promise,” said Gianneschi.

Unfortunately, the peptide had several limitations. Peptides have a short lifespan in the body as they are easily broken down by enzymes, and often face difficulty entering cells. To be effective for Huntington’s disease, the peptide would need to be able to cross the blood–brain barrier in large quantities.

“The peptide has a very small footprint with respect to the protein interfaces. 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,” said Gianneschi.

Developing a biocompatible polymer

To overcome the peptide’s limitations, Gianneschi and the team developed a biocompatible polymer that displays multiple copies of the active peptide. The new structure has a polymer backbone with peptides attached like branches, protecting the peptides from destructive enzymes and helping them cross the blood–brain barrier and enter cells.

To test the polymer, the team injected the protein-like substance into Huntington’s disease mouse models. The polymers remained in the body 2,000 times longer than traditional peptides, and biochemical and neuropathological examinations indicated the treatment prevented mitochondrial fragmentation. The mice with Huntington’s disease lived longer than the control mice that did not receive the polymer. They also displayed behaviors similar to healthy mice.

“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,” said Gianneschi.

Continuing to optimize the polymer

The polymer also demonstrated an extended elimination half-life of ~152 hours, and showed no toxicity, even with high, continuous dosing over 8 weeks. This extended half-life is promising for potential low-dose or single-dose treatments and could allow sustained, low-dose continuous administration in future applications.

The team plan to continue to optimize the polymer, as well as explore its potential use in other neurodegenerative diseases.

“My childhood friend was diagnosed with Huntington’s at age 18 through a genetic test. 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,” said Gianneschi.

Reference: Choi W, Fattah M, Shang Y, et al. Proteomimetic polymer blocks mitochondrial damage, rescues Huntington’s neurons, and slows onset of neuropathology in vivo. Sci Adv. 2024. doi: 10.1126/sciadv.ado8307

This article is a rework of a press release issued by Northwestern University. Material has been edited for length and content.