Abstract:
The invention provides methods for delivering a double-stranded nbonucleic acid (dsRNA) to the central nervous system of a subject, and particularly, to oligodendrocytes of a subject by localized delivery to the brain, e.g., to the corpus caïlosum. For example, the dsRNA molecules can include a first sequence that is selected from the Sroup consisting of the sense sequences of Tables 8, 10, 13-16, and a second sequence selected from the group consisting of the antisense sequences of Tables 8, 10, and 13-16. The dsRNA molecules can include naturally occurring nucleotides or can include at least one modified nucleotide, such as a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, or a terminal nucleotide linked to a conjugate group, such as to a cholesteryl derivative or a vitamin E group. Alternatively, the modified nucleotide may be chosen from the group consisting of a 2f-deoxy-2′-fliιioro modified nucleotide, a 2′-de-oxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural bas comprising nucleotide. Generally, such modified sequences will be based on a first sequence of a dsRNA selected from the group consisting of the sense sequences of Tables 8, 10, and 13-16, and a second sequence selected from the group consisting of the antisense sequences of Tables 8 10, and 13-16.