New methods promise to treat Huntington’s disease

Recently, Li Shihua, Yan Sen and Li Xiaojiang of the Guangdong-Hong Kong-Macao Institute of Central Nervous Regeneration of Jinan University successfully constructed a Mini-intrabody, which can specifically bring mutant huntingtin protein into lysosomes for degradation and reduce the accumulation of toxic proteins, which is expected to provide a new scheme for the treatment of huntington’s disease. The results were published online in Advanced Science. Li Shihua, Yan Sen and Li Xiaojiang are the co-corresponding authors of the paper, and Li Caijuan and Lin Yingqi are the co-first authors.

Summary diagram of intrabody treatment of Huntington’s disease (KI-140Q) mice. Photo courtesy of the research team

Huntington’s disease is a single-gene mutation-dominantly inherited neurodegenerative disease caused by the accumulation of mutant huntingtin protein in cells. Mutated huntingtin proteins cause neuronal damage and death in the central nervous system. The accumulation of misfolded proteins is the main and common cause of many neurodegenerative diseases, so the most direct and effective way to treat these diseases is to reduce or eliminate the level of mutant proteins.

The researchers constructed a mini-intrabody peptide (SM3), which can recognize and bind the huntingtin protein and then bring the huntingtin protein into the lysosome, thereby achieving the purpose of degrading the huntingtin protein by activating the lysosomal autophagy pathway. The results showed that the delivery of AAV-SM3 by stereotactic brain injection and orbital intravenous injection effectively reduced the soluble and insoluble huntingtin protein in the brains of mice with Huntington’s disease, and effectively improved neuropathological and motor disorders such as glial hyperplasia associated with Huntington’s disease. Overall, SM3 offers a new therapeutic strategy for treating Huntington’s disease in adulthood.

The pathological and clinical manifestations of patients with Huntington’s disease worsen with age. Mini-intrabody’s research provides a potential small molecule therapy for the treatment of the middle and later stages of Huntington’s disease, and also provides new ideas and treatments for the treatment of other neurodegenerative diseases caused by protein misfolding, such as AD, PD and ALS.

The above research has been strongly supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Guangzhou Brain Science Key Research Program, Jinan University, Guangdong Provincial Science and Technology Department, Guangzhou Science and Technology Bureau, and Guangdong Provincial Key Laboratory of Nonhuman Primate Model Research. (Source: China Science News Zhu Hanbin)

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