免疫介在性神経疾患治療における核酸医薬の可能性

抄録

Given that immune–mediated neurological disorders are caused by inadequate immune response, manipulating the functions of immune cells represents a promising treatment. Monoclonal antibody therapy and oligonucleotide therapy target specific molecules via different mechanisms of action.

Some clinical studies for immune–mediated disorders of antisense oligonucleotides (ASO), short interfering RNA, and oligonucleotide aptamers have been already initiated. Though lymphocytes are important players in immune–mediated disorders, regulating these functions is challenging because lymphocytes are highly resistant to transfection. Therefore, efficient drug delivery technology for conventional oligonucleotides is required. We developed DNA/RNA heteroduplex oligonucleotide (HDO), which is comprised of ASO and delivery ligand conjugated–complementary RNA. Notably, α–tocopherol (vitamin E) binding HDO has achieved efficient delivery into hepatocytes and brain microvascular endothelial cells compared with the parent ASO.

Although some monoclonal antibody drugs are approved for immune–mediated neurological disorders, these drugs can't control the intracellular molecules of immune cells, such as lymphocytes and microglia. Unlike monoclonal antibody drugs, oligonucleotide drugs have the potential to manipulate the functions of immune cells by modulating the endogenous gene expression including non–coding RNAs, such as some micro–RNAs, involved in pathophysiological processes. The development of oligonucleotide therapy with high potency for immune–mediated neurological disorders is desired.