Oligonucleotides for tissue specific ApoE modulation

A branched oligonucleotide compound comprising two or more nucleic acids, wherein:

• each nucleic acid comprises 15 to 50 bases in length,
• each nucleic acid comprises a double stranded RNA (dsRNA) comprising a sense strand and an antisense strand,
• each antisense strand independently comprises a region of complementarity of at least 14 contiguous nucleotides which is 100% complementary to SEQ ID NO:
• 5 or a region of complementarity of at least 14 contiguous nucleotides which is 100% complementary to SEQ ID NO:
• 6, and
• the two or more nucleic acids are covalently connected to one another.

A branched oligonucleotide compound comprising two or more nucleic acids, wherein:

• each nucleic acid comprises 15 to 50 bases in length,
• each nucleic acid comprises a double stranded RNA (dsRNA) comprising a sense strand and an antisense strand,
• the sense strand has a sequence as set forth in SEQ ID NO:
• 4, and
• the two or more nucleic acids are covalently connected to one another.

A compound of formula (I):

• wherein:
• L comprises an ethylene glycol chain, an alkyl chain, a peptide, an RNA, a DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or combinations thereof;
• N is a double stranded RNA (dsRNA) comprising 15 to 35 bases in length comprising a sense strand and an antisense strand, wherein:
• the antisense strand comprises a region of complementarity of at least 14 contiguous nucleotides which is 10000 complementary to SEQ ID NO:
• 5 or a region of complementarity of at least 14 contiguous nucleotides which is 100% o complementary to SEQ ID NO:
• 6, and
• the sense strand and the antisense strand each independently comprises one or more chemical modifications;
• and
• n is 2, 3, 4, 5,6, 7, or 8.

A di-branched RNA compound comprising:

• two RNA molecules each comprising 15 to 50 bases in length,
• wherein each RNA molecule comprises a double stranded RNA (dsRNA) comprising a sense strand and an antisense strand,
• wherein the sense strand has a sequence as set forth in SEQ ID NO:
• 4, and
• wherein the two RNA molecules are connected to one another by one or more moieties independently selected from a linker, a spacer and a branching point.