Antisense compounds targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of parkinsons disease
The present disclosure relates generally to compounds comprising oligonucleotides complementary to a Leucine-Rich-Repeat-Kinase (LRRK2) RNA transcript. Certain such compounds are useful for hybridizing to a LRRK2 RNA transcript, including but not limited to a LRRK2 RNA transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the LRRK2 transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Parkinson's disease.
1. A method of modulating splicing or expression of a Leucine-Rich-Repeat-Kinase (LRRK2) transcript in a cell comprising contacting the cell with a compound or pharmaceutical composition comprising a modified oligonucleotide having 8 to 30 linked nucleosides, and having a nucleobase sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2; wherein the nucleobase sequence comprises a complementary region with at least 8 contiguous nucleobases complementary to an equal-length portion of a target region of the LRRK2 transcript.
2. The method of claim 1 , wherein the cell is in vitro or in vivo.
3. The method of claim 1 , wherein the cell is in vivo in an animal, and the animal is a human.
4. The method of claim 3 , wherein the modified oligonucleotide is administered to the human by intrathecal injection, intracerebroventricular injection, inhalation, parenteral injection or infusion, oral, subcutaneous or intramuscular injection, buccal, transdermal, transmucosal or topical.
5. The method of claim 1 , wherein the target region of the modified oligonucleotide comprises at least a portion of exon 31 or exon 41 of the LRRK2 transcript.
6. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside selected from a modified sugar moiety, a 2′-substituted sugar moiety, a 2′OME, a 2′F, a 2′-MOE, a bicyclic sugar moiety, a LNA, a cEt, a sugar surrogate, a morpholino, or a modified morpholino.
7. The method of claim 1 , wherein the complementary region of the modified oligonucleotide comprises 10-25 contiguous nucleobases.
8. The method of claim 4 , wherein the modified oligonucleotide is administered by intrathecal injection.
9. The method of claim 4 , wherein the modified oligonucleotide is administered by intracerebroventricular injection.
10. The method of claim 5 , wherein the target region of the modified oligonucleotide comprises at least a portion of exon 41 of the LRRK2 transcript.
11. The method of claim 1 , wherein the modified oligonucleotide consists of the nucleobase sequence as set forth in SEQ ID NO: 2.
12. The method of claim 6 , wherein the modified nucleoside is a morpholino.
13. The method of claim 3 , wherein the human has one or more symptoms associated with Parkinson's disease.
14. The method of claim 1 , wherein the modified oligonucleotide has 8 to 25 linked nucleosides.