Don Cleveland - Designer DNA Drug Therapy for Neurodegenerative Disease

Professor Cleveland discussed the molecular mechanisms underlying various gene mutations associated with neurodegenerative diseases and the use of antisense oligonucleotides (ASOs) in treating these conditions. Professor Cleveland's team discovered that ASOs can enter neurons and selectively pair with mRNA, resulting in RNA degradation and the inhibition of gene expression. Leveraging this feature, the team designed various ASO-based therapeutic strategies to address neurodegenerative diseases caused by gain-of-function gene mutations. He then provided examples of recent research achievements by his team. For instance, around 2% of individuals with Amyotrophic Lateral Sclerosis (ALS) develop the disease due to the toxic effects of functionally mutated SOD1 genes. ASO-SOD1 was effective in reducing SOD1 expression. Similarly, Parkinson's disease caused by activating mutations in the LRRK2 gene could be targeted with ASO-LRRK2. Additionally, Alzheimer's disease related to the accumulation of misfolded Tau protein could be addressed with ASO-Tau. Professor Cleveland also shared applications of ASOs in guiding normal gene expression in ALS and Frontotemporal Dementia (FTD). For example, ASO drugs could partially replace the function of TDP-43, restoring normal splicing of STMN2 pre-mRNA and thereby normalizing the synthesis of Stathmin-2 protein. In conclusion, Professor Cleveland summarized the progress and prospects of DNA drugs in treating neurodegenerative diseases within the nervous system.