Compositions and methods for improved gene silencing

Abstract

The present disclosure provides single- or double-stranded interfering RNA molecules (e.g., siRNA) that exhibit improved gene silencing. The disclosure provides siRNA molecules having a fixed nucleobase region. For example, the antisense strand of the siRNA molecule may have a nucleobase region that contains one or more mismatches relative to the target mRNA molecule. Alternatively, or in addition, the antisense strand may contain a region of nucleobases having a sequence that is independent of the target mRNA. The fixed region may be contained within an overhang region of the antisense strand. The siRNA molecules may contain specific patterns of nucleoside modifications and internucleoside linkage modifications, as pharmaceutical compositions including the same. The siRNA molecules may be branched siRNA molecules, such as di-branched, tri-branched, or tetra-branched siRNA molecules. The disclosed siRNA molecules may further feature a 5′ phosphorus stabilizing moiety and/or a hydrophobic moiety. Additionally, the disclosure provides methods for delivering the siRNA molecule of the disclosure to the central nervous system of a subject, such as a subject identified as having a neurodegenerative disease.

Dependencies are inferred from the claim text.