Antisense compounds targeting Leucine-Rich repeat kinase 2(LRRK2) for the treatment of Parkinsons disease
Inventors
Hastings, Michelle L. • Isacson, Ole • Korecka-Roet, Joanna A.
Assignees
Rosalind Franklin University of Medicine and Science • Mclean Hospital Corp
Publication Number
US-10787669-B2
Publication Date
2020-09-29
Expiration Date
2036-11-11
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Abstract
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.
Core Innovation
The invention discloses compounds comprising modified oligonucleotides that are complementary to specific regions of the Leucine-Rich-Repeat-Kinase 2 (LRRK2) RNA transcript. These antisense compounds are designed to hybridize to distinct target regions of the LRRK2 transcript, such as exon 2, exon 4, exon 31, or exon 41. By binding to these regions, especially splice sites, the compounds modulate splicing, resulting in either nonsense mRNAs or mRNAs that code for LRRK2 proteins with reduced kinase activity.
The background section describes Parkinson's disease (PD) as a motor system disorder resulting from the loss of dopamine-producing brain cells and highlights that there is no cure for PD. Current therapies provide only symptomatic relief, and there is an unmet need for more effective treatments. Genetic factors, specifically mutations in the LRRK2 gene (notably G2019S and R1441C), are a significant cause of familial and sporadic PD cases.
The present disclosure provides antisense oligonucleotides (ASOs) that block the splicing of LRRK2 transcripts at critical exons. For instance, ASOs that induce skipping of exon 41 (containing the G2019S mutation) or exon 31 (containing the R1441C mutation) lead to the production of alternative LRRK2 isoforms with diminished pathogenic activity or eliminate expression of mutated LRRK2. These ASOs are claimed to reduce full-length LRRK2 expression and be useful for treating one or more symptoms associated with Parkinson's disease.
Claims Coverage
The independent claims of the patent focus on chemical compositions of modified antisense oligonucleotides and pharmaceutical compositions containing them, targeting specific sequences of the LRRK2 RNA transcript.
Modified oligonucleotide targeting LRRK2 transcripts
A compound comprising a modified oligonucleotide having 16 to 30 linked nucleosides, wherein the nucleobase sequence comprises at least 16 contiguous nucleobases of any of the sequences SEQ ID NO:01, SEQ ID NO:02, SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, or SEQ ID NO:09.
Modified oligonucleotide complementary to LRRK2 transcript splice site
A compound wherein the oligonucleotide comprises a complementary region to a target region of a LRRK2 transcript, and the target region includes a splice site.
Pharmaceutical composition containing the antisense compound
A pharmaceutical composition comprising at least one of the modified oligonucleotides as described and a pharmaceutically acceptable carrier or diluent.
Modified oligonucleotide with specific sequence range
A compound comprising a modified oligonucleotide having 25 to 30 linked nucleosides comprising a nucleobase sequence selected from SEQ ID NO:01, SEQ ID NO:02, SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, and SEQ ID NO:09.
The inventive features protect antisense oligonucleotides with specified sequence lengths and chemical modifications targeting defined regions (including splice sites) of the LRRK2 transcript, as well as pharmaceutical compositions comprising these compounds.
Stated Advantages
ASOs targeting LRRK2 induce specific exon skipping, resulting in reduction of full-length LRRK2 expression or production of LRRK2 isoforms with lower kinase activity.
Administration of these compounds can ameliorate or treat one or more symptoms associated with Parkinson's disease.
These compounds provide a potential therapeutic approach addressing the genetic cause of PD, which is not addressed by current symptomatic treatments.
Documented Applications
Treatment or amelioration of symptoms associated with Parkinson's disease in humans or animals carrying LRRK2 mutations.
Modulation of splicing or expression of LRRK2 transcripts in cells, both in vitro and in vivo.
Use in pharmaceutical compositions for administration via routes including intracerebroventricular injection, inhalation, parenteral, oral, subcutaneous, intramuscular, buccal, transdermal, transmucosal, and topical.
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