A research team led by Distinguished Professor Tzu-Hao Cheng at National Yang Ming Chiao Tung University has successfully developed a SUPT4H inhibitor based on molecular mechanisms, demonstrating its potential to slow the progression of Huntington’s Disease (HD) in cellular and animal experiments.

New Therapy for HD Patients: SUPT4H Inhibitor

Huntington’s Disease is a genetic neurodegenerative disorder for which no effective treatment currently exists. Patients experience symptoms such as motor coordination issues, rapid limb movements, cognitive decline, and personality changes. As the disease progresses, patients eventually succumb to respiratory failure or other complications. Professor Cheng's team has been dedicated to researching treatments for neurodegenerative diseases. Previous studies found that the SUPT4H protein plays a crucial role in regulating the expression of the mutant HTT gene, which causes HD. Thus, inhibiting SUPT4H activity could potentially reduce the expression of the mutant HTT gene and slow disease progression.

In their latest research, Professor Cheng’s team, in collaboration with Stanford University, used a high-throughput cell screening platform to identify the small molecule compound 6-AZA as a SUPT4H inhibitor. They further demonstrated in cellular and animal experiments that 6-AZA effectively reduces the expression of the mutant HTT gene, improves HD pathological features, and slows disease progression.

Cellular Experiments Confirm Pathology Improvement, Animal Experiments Confirm Slowing of Disease Progression

In cellular experiments, the team used striatal neuronal cell lines from transgenic mice and induced pluripotent stem cells (iPSCs) from HD patients to show that 6-AZA reduces the RNA and protein expression of the mutant HTT gene. Additionally, they used CRISPR/Cas9 technology to modify the length of the mutant HTT gene in HD iPSCs to normal lengths, confirming that the mutant HTT suppresses the expression of antioxidant stress genes in neuronal cells, thus reducing the cells' ability to combat oxidative stress. 6-AZA can restore the expression of antioxidant stress genes by downregulating the mutant HTT gene, improving neuronal cell survival under oxidative stress.

In animal experiments, Professor Cheng’s team tested the efficacy of 6-AZA using an HD fruit fly model. The results showed that 6-AZA effectively reduces the expression of the mutant HTT gene and significantly decreases the number of white-eyed decayed fruit flies.

Market Potential for SUPT4H Inhibitors and Concurrent Development of Diagnostic Services

Professor Cheng noted that the development of the SUPT4H inhibitor also led to the creation of rapid, precise, and stable detection platforms. Thus, besides new drug development, related diagnostic services such as protein and gene testing could also be offered in the future. The team is currently working on improving the pharmacological properties of 6-AZA and hopes to push optimized derivative drugs into clinical trials, bringing new hope for treatment to HD patients.

Resource (mandarin): 攻克亨氏舞蹈症候群！陽明交大團隊研發SUPT4H抑制劑，延緩細胞氧化速度！