New potential therapeutic platform to treat Huntington’s disease
Huntington’s disease (HD) is a neurodegenerative condition that gradually leads to the breakdown and death of nerve cells in the brain. Symptoms include significant cognitive decline, emotional instability, clumsiness, balance issues, and poor coordination, all of which severely impact a patient’s quality of life. The global prevalence of HD is around 3 % per 100,000 people, with a much higher incidence in the United States and Europe. HD is also hereditary, meaning that children of an affected parent have a 50% risk of inheriting the disease. Despite its impact, there is still no effective cure for HD, and multiple research efforts are underway to address this gap.
HD develops when there are more than 39 repeats of a specific DNA sequence (CAG) in the Huntingtin (Htt) gene. This expansion results in an abnormal version of the huntingtin protein (mthtt), which damages structures within cells called mitochondria. These abnormal proteins bind to a specific molecule on mitochondria known as valosin-containing protein (VCP), leading to a buildup of harmful VCP. This accumulation causes nerve cells to die, contributing to HD’s characteristic involuntary movements. Additionally, HD patients often have low levels of critical brain chemicals due to the loss of these neurons. Researchers believe that targeting the interaction between the abnormal huntingtin protein and VCP may help prevent this accumulation and potentially save nerve cells. Indeed, scientists have already shown that this harmful interaction can be disrupted using a specially designed peptide, a small chain of amino acids that can penetrate cells, called HV3-TAT. However, enzymes in the body quickly break down this peptide, limiting its therapeutic potential.
In a recent study, researchers at Northwestern and Case Western Reserve Universities incorporated polymers—large molecules made of repeating units—into HV3 to create a new version with a “protein-like” structure. This structure helps protect the peptide from breakdown, allowing it to reach its target more effectively. The scientists rigorously tested this polymer-peptide combination as a potential treatment for HD. First, they confirmed that this polymer-peptide could reach the mitochondria, where it successfully blocked the harmful interaction between VCP and mthtt. Second, they demonstrated that the polymer-peptide complex remains stable over time, allowing it to be detected in various organs—unlike HV3-TAT, which becomes undetectable after only five minutes. Third, the researchers found that this new polymer-drug complex could reduce HD symptoms, like weight loss and limb clasping, in mice. Finally, treatment with the polymer-peptide complex increased levels of important brain chemicals in HD models, marking another improvement over HV3-TAT. Overall, these findings suggest that the polymer-peptide complex can block the VCP/mthtt interaction and represent a promising step toward developing an HD treatment.
Future studies aim to refine this therapeutic approach so it can cross the blood-brain barrier, which is crucial for effective treatment in living systems. Researchers are also exploring whether this method could apply to other neurodegenerative diseases. In their report, the scientists emphasize the potential of using polymers as therapies themselves, rather than as carriers for other drugs.
References:
Choi, W.; Fattah, M.; Shang, Y.; Thompson, M. P.; Carrow, K. P.; Hu, D.; Liu, Z.; Avram, M. J.; Bailey, K.; Berger, O.; Qi, X.; Gianneschi, N. C., Proteomimetic polymer blocks mitochondrial damage, rescues Huntington’s neurons, and slows onset of neuropathology in vivo. Science Advances 10 (44), eado8307.
Pringsheim, T.; Wiltshire, K.; Day, L.; Dykeman, J.; Steeves, T.; Jette, N., The incidence and prevalence of Huntington's disease: A systematic review and meta-analysis. Movement Disorders 2012, 27 (9), 1083-1091.