COMPOSITIONS AND METHODS FOR DELIVERING THERAPEUTIC OLIGONUCLEOTIDES TO THE CENTRAL NERVOUS SYSTEM

The present disclosure provides single- or double-stranded therapeutic oligonucleotides (e.g., siRNAs, shRNAs, miRNAs, gRNAs, and ASOs) having a plurality of cationic binding sites that are partially or fully saturated by a plurality of divalent cations (e.g., Ba2+, Be2+, Ca2+, Cu2+, Mg2+, Mn2+, Ni2+, or Zn2+, or a combination thereof). The therapeutic oligonucleotides 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 disease.