DUAL-ACTING siRNA BASED MODULATION OF C9orf72
AssigneeUniversity of Massachusetts
InventorsAnastasia Khvorova, Bruno Miguel da Cruz Godinho, James W. Gilbert
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Abstract
This disclosure relates to novel C9ORF72 targeting sequences. Novel sense and antisense dual-targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.
Claims52
A double-acting RNA silencing agent comprising a first oligonucleotide strand and a second oligonucleotide strand, each strand comprising a 5′ end and a 3′ end, wherein the first strand inhibits expression of a C9ORF72 sense transcript and the second strand inhibits expression of a C9ORF72 antisense transcript, wherein the first and second oligonucleotide strand are substantially complementary to a non-repeat region in the C9ORF72 sense and antisense transcript.
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A branched oligonucleotide compound comprising at least two double-acting RNA silencing agents, wherein each double-acting RNA silencing agent comprises:
- a first guide strand comprising a 5′ end and a 3′ end, and
- a second guide strand comprising a 5′ end and a 3′ end, wherein the at least two double-acting RNA silencing agents are connected to one another by one or more moieties comprising a linker, a spacer, or a branching point.
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A double-acting, double stranded (ds) RNA comprising a first guide strand and a second guide strand, wherein at least one nucleotide is mismatched between the first strand 5′ end and second strand 3′ end, and at least one nucleotide is mismatched between the first strand 3′ end and second strand 5′ end, wherein the first guide strand inhibits expression of a sense mRNA target and the second guide strand inhibits expression of an antisense mRNA target.
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Dependencies are inferred from the claim text.