New genetic strategy found to fight Huntington's disease

14.07.2023

Researchers at the University of Padua identify a potential therapeutic strategy for Huntington's disease. As the most widespread neurodegenerative disorder of genetic origin among the Caucasian population, there is no effective therapy available for Huntington's disease. Recently published in Nature Communications, entitled Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity is the result of the work by the research group led by Prof Graziano Martello of the Department of Biology of the University of Padua who also heads the Laboratory of Pluripotent Stem Cell Biology, which is funded by the Telethon and Armenise-Harvard Foundations.

At the root of Huntington's disease is a genetic defect that stems from the accumulation of a protein called huntingtin, which over time, results in the progressive death of cells in specific areas of the brain. Initial symptoms range from abrupt changes in mood, apathy and depression, to progressive unsteadiness and lack of motor coordination. The cause of this genetic defect has been known for over 30 years and, thanks to the work of researchers from all over the world, and many aspects of the neurodegenerative process has been clarified. However, to date, there are no therapies to counteract its damage.

Using stem cells grown in the laboratory as a model of the disease, researchers at the University of Padua have scanned the entire human genetic heritage in search of genes capable of protecting diseased cells.

Co-author and researcher Giorgia Ferlazzo, who dedicated her doctorate in Molecular Medicine to this project, explains, “Holding the same genetic mutation responsible for the pathology in humans, we use zebrafish and mice models to study Huntington's disease. Here, we identified that Mtf1 has a protective ability, and supplied this gene to the cells through viral vectors or genetic instructions in the form of messenger RNA (mRNA), which led to an improvement or even the arrest of the development of the disease in both models.”

Comments from the Neuroscience PhD student Sonia Amato, who equally contributed to the work along with Anna Gambetta, “These positive results were also confirmed in a human model, thanks to a stem cell sample donated by a patient. In this case, we obtained a sample of diseased neuronal cells from a patient and as a result Mtf1 proved to be able to reduce some of the characteristic defects of Huntington's disease. Such encouraging results pushes us to continue on this road to develop a new therapeutic strategy in the future.

Prof Martello concludes, “While the road to therapy in patients remains far, we must improve the way these therapeutic genes are delivered to humans first. In animal models we used viral vectors or mRNAs, those tools that have become commonly used for vaccines against COVID-19. Now we are interested in understanding whether these tools are also suitable for the treatment of neurodegenerative diseases.