シヌクレイノパチーの次世代治療

抄録

In synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), accumulation and aggregation of α–synuclein (SNCA) trigger cytotoxicity and neurodegeneration. When treating synucleinopathies, a therapy to exogenously compensate for dopamine deficiency in the brain due to the degeneration of dopaminergic neurons, has become most common. However, the treatment is not immune to decreased drug efficacy with disease progression. In contrast, if a therapy targeting SNCA, which constitutes the essential disease condition for synucleinopathies, became available, it could be a fundamental treatment that suppresses the progression of neuronal degeneration. In line with the rapid progress in nucleic acid modification techniques, a therapeutic approach that prevents the production of target proteins using nucleic acids medicine has become available. Our group is attempting to treat PD using nucleic acid medicine targeting SNCA. We use Gamper–type antisense oligonucleotides (ASOs) that incorporate a novel nucleic acid modification, amino–bridged nucleic acids (AmNA). These AmNA–ASOs have the advantages of enhanced binding capacity and stability, as well as reduced toxicity. In our previous studies, we optimized the sequence and structure of ASOs that most effectively suppresses SNCA mRNA. By administration into lateral ventricles in mouse models of PD, the ASO was efficiently delivered into mouse brains. Furthermore, the ASO suppressed the levels of SNCA in the striatum of mouse models and improved their motor symptoms. We are currently testing the efficacy and safety of the ASO in non–human primate to proceed this therapeutic approach to clinic, especially for familial PD (PARK4) that is caused by SNCA overexpression. If we can establish an SNCA suppression treatment for PARK4 using ASO, this therapy might eventually be applied to all kinds of synucleinopathies and serve as a groundbreaking disease–modifying therapy.