Progressive multifocal leukoencephalopathy (PML) is a rare, fatal demyelinating disease of the brain caused by the polyomavirus JC (JCV) under immunosuppressive conditions. It is pathologically characterized by progressive damage of white matter of the brain by destroying oligodendrocytes at multiple locations. Clinically, PML symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. The prognosis of PML is generally poor. No effective therapy for PML has been established. The current strategies to develop a PML therapy focus on blocking viral infection or inhibiting JCV replication. Antisense oligodeoxynucleotides (ODNs) that can block JCV replication and multiplication have been identified and optimized. Use of the ODNs provide a method of inhibiting JCV replication and thereby provide a treatment for PML.