Antisense oligonucleotide for targeting progranulin
The present invention relates to oligonucleotides which alter the splicing pattern of progranulin in cells, and their use in the treatment of neurological disorders.
1. An antisense oligonucleotide consisting of a contiguous nucleotide sequence, which is complementary to a splice regulation site of the human progranulin pre-mRNA transcript, wherein the contiguous nucleotide is SEQ ID NO:134, and wherein the antisense oligonucleotide or contiguous nucleotide sequence thereof comprises one or more modified nucleotides or one or more modified nucleosides.
2. The antisense oligonucleotide according to claim 1 , wherein the contiguous nucleotide sequence is complementary to SEQ ID NO:281.
3. The antisense oligonucleotide according to claim 1 , wherein the antisense oligonucleotide is or comprises an antisense oligonucleotide mixmer or totalmer.
4. An antisense oligonucleotide having the structure:
5. An antisense oligonucleotide wherein the oligonucleotide is the oligonucleotide CtcAagCtcAcAtgGC (SEQ ID NO:134) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.
6. A pharmaceutical composition comprising the antisense oligonucleotide according to claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
7. The antisense oligonucleotide according to claim 1 for use in the treatment of a neurological disease.
8. The antisense oligonucleotide according to claim 1 for use in the treatment of progranulin haploinsufficiency or a related disorder.
9. The pharmaceutical composition according to claim 6 for use in the treatment of a neurological disease.
10. The pharmaceutical composition according to claim 6 for use in the treatment of progranulin haploinsufficiency or a related disorder.