The present disclosure provides single-stranded or double-stranded interfering
RNA molecules (e.g., siRNAs) that exhibit improved
gene silencing. The present disclosure provides siRNA molecules having a fixed
nucleobase region. For example, the antisense strand of the siRNA molecule may have a
nucleobase region containing one or more mismatches relative to a
target mRNA molecule. Alternatively or additionally, the antisense strand may contain a
nucleobase region having a sequence independent of the
target mRNA. An immobilization region may be included within a protruding end region of the antisense strand. The siRNA molecule may contain a specific pattern of
nucleoside modification and a
nucleoside-to-
nucleoside linkage modification, as a pharmaceutical composition comprising the siRNA molecule. The siRNA molecule may be a branched siRNA molecule, such as a two-branched, three-branched or four-branched siRNA molecule. The disclosed siRNA molecules may further be characterized by a 5 '-
phosphorus stabilizing
moiety and / or a
hydrophobic moiety. In addition, the present disclosure provides methods for delivering siRNA molecules of the present disclosure to a subject, such as the
central nervous system of a subject identified as having a neurodegenerative
disease.