Discovery of a Potential New Therapeutic Target for Huntington’s Disease with AAV

Huntington’s disease (HD), also known as chronic progressive chorea, is a hereditary neurodegenerative disorder with a slow onset. The main clinical manifestations include uncontrollable grimacing, nodding, finger movements, psychiatric disorders, and cognitive impairment. Patients typically die 15-20 years after onset. Current treatments are limited to symptom management, with no methods available to prevent or slow the disease’s progression. Hence, it is referred to in the medical community as the “dance of death.”

HD is an autosomal dominant genetic disorder with a global prevalence of approximately 2.7/100,000 and an incidence rate of about 0.38/100,000 annually. The prevalence is around 5.7/100,000 in Europe, North America, and Australia, and about 0.4/100,000 in Asia. The causative gene for HD is the huntingtin gene (HTT), which encodes a large protein with over 3,000 amino acids. An abnormal expansion of CAG trinucleotide repeats in the first exon of HTT leads to misfolding of the huntingtin protein (mHTT). This mutated protein accumulates in the brain, ultimately causing neurological dysfunction and degeneration. Targeting the suppression of mHTT expression may be key to treating Huntington’s disease.

On May 17, 2024, Professors Xiaojiang Li and Su Yang from Jinan University published their latest research findings in the journal Science Advances. Their study reported previously unidentified pathogenic mechanisms of HTT and discovered a primate-specific E3 ubiquitin ligase, TRIM37. TRIM37 promotes the ubiquitination and degradation of mutant HTT (mHTT) and regulates its aggregation in the brains of mice and monkeys. Therefore, TRIM37 protein can be considered a potential therapeutic target for Huntington’s disease by modulating mHTT expression. PackGene provided AAV packaging services for this study.

Figure 1: TRIM37 regulates mHTT aggregation in vivo

References:
https://pubmed.ncbi.nlm.nih.gov/38758800/