Oligomers targeting hexanucleotide repeat expansion in human c9orf72 gene
AssigneePfizer Inc.
InventorsMads Aaboe Jensen, Morten Lindow
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Abstract
The disclosure relates to oligomers capable of targeting RNA expressed from the human C9ORF72 gene containing a pathogenic hexanucleotide repeat expansion. Such oligomers are useful for, among other things, reducing or eliminating C9ORF72 RNA and/or proteins translated therefrom, and treating or preventing diseases or disorders caused by, or associated with, hexanucleotide repeat expansion, including familial frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS).
Claims18
A gapmer comprising between 12 to 30 nucleosides, complementary to at least a 12 contiguous nucleobase portion of SEQ ID NO:187, wherein the gapmer further comprises in 5′ to 3′ order:
- (a) a 5′ flanking region consisting of 1 to 5 contiguously linked nucleosides, at least one of which is an LNA monomer,
- (b) a gap region consisting of contiguously linked deoxyribonucleosides;
- and
- (c) a 3′ flanking region consisting of 1 to 5 contiguously linked nucleosides, at least one of which is an LNA monomer.
- wherein the gapmer is capable of preferentially inhibiting expression of C9ORF72 sense transcript containing an expanded hexanucleotide repeat region when compared with inhibiting expression of a wild-type C9ORF72 sense transcript, and
- wherein the gapmer is further capable of inhibiting expression of C9ORF72 antisense transcript containing an expanded hexanucleotide repeat region.
The gapmer of any of the preceding claims, wherein all internucleoside linkages are phosphorothioate.
A gapmer consisting of 14 nucleotides wherein the nucleobase sequence consists of the sequence of SEQ ID NO:109, and the 5′ flanking region consists of two nucleosides that are LNA monomers, the 3′ flanking region consists of three nucleosides that are LNA monomers, wherein all internucleoside linkages are phosphorothioate linkages, and each cytosine at positions 6 and 12 is a 5-methylcytosine.
A composition comprising the gapmer of any of the preceding claims and a pharmaceutically acceptable carrier.
A method of treating a disorder in a subject in need thereof wherein the subject is suffering from a disease or disorder mediated by or associated with repeat expansion in a C9ORF72 sequence, comprising administering to said subject a therapeutically effective amount of the gapmer of any of the preceding claims.
Dependencies are inferred from the claim text.