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-10370667-B2
Publication Date
2019-08-06
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 provides compounds comprising oligonucleotides that are complementary to a Leucine-Rich-Repeat-Kinase 2 (LRRK2) RNA transcript. These antisense oligonucleotides (ASOs) are designed to hybridize to specific regions of the LRRK2 transcript, including but not limited to exon 2, exon 4, exon 31, and exon 41. Hybridization of these ASOs to the target transcript modulates splicing, resulting in altered mRNA products that either eliminate mutated exons or induce frameshifts that disrupt LRRK2 protein production.
The problem addressed by this invention lies in the limitations of existing Parkinson's disease (PD) treatments, which do not cure the disease and often inadequately alleviate symptoms caused by LRRK2 mutations. Mutations in the LRRK2 gene, such as G2019S and R1441C, are prominent genetic contributors to familial and sporadic PD. Current therapies only partially address symptoms and do not target the underlying genetic defects.
This disclosure introduces the use of chemically modified antisense oligonucleotides that specifically bind to and block splicing at key exons (exon 2, 4, 31, or 41) of LRRK2 pre-mRNA. Blocking splicing at these exons can remove pathogenic mutations, restore normal or partially functional LRRK2 protein, or reduce the levels of the toxic mutant protein. The invention includes various modifications to the ASOs to optimize their stability and efficacy, and further contemplates pharmaceutical compositions and therapeutic methods for modulating splicing or expression of LRRK2 in vitro and in vivo, including use for the treatment of symptoms associated with Parkinson's disease.
Claims Coverage
The patent claims focus on methods involving modified oligonucleotides that target LRRK2 transcripts for modulating splicing or expression, covering key composition and application features.
Modulating splicing or expression of LRRK2 transcript using specific modified oligonucleotide
A method comprising contacting a cell with a compound that includes a modified oligonucleotide of 8 to 30 linked nucleosides with a nucleobase sequence comprising a complementary region. This region consists of at least 8 contiguous nucleobases complementary to an equal-length portion of a target region of a LRRK2 transcript. The oligonucleotide has a nucleobase sequence as set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8. The inventive feature includes: - The use of modified oligonucleotides with specific chemical modifications (such as modified sugar moieties, 2'-OME, 2'-F, 2'-MOE, bicyclic sugar moieties, LNA, cEt, sugar surrogates, morpholino, or modified morpholino). - Spanning complementary regions of 10-25 contiguous nucleobases. - Optionally targeting at least a portion of exon 2, exon 4, exon 31, or exon 41 of the LRRK2 transcript.
Sequence-specific composition for modulating LRRK2 splicing
The invention covers using a modified oligonucleotide with a specific nucleobase sequence consisting of SEQ ID NO:7, SEQ ID NO:6, SEQ ID NO:8, or SEQ ID NO:9 for modulating LRRK2 splicing events. Distinctive points include: - The oligonucleotide is sequence-specific and may be entirely made of the claimed sequence. - The compound may further comprise a pharmaceutically acceptable carrier or diluent for in vivo use.
Therapeutic methods of administration
The claims cover the administration of the modified oligonucleotide to humans or animals by intrathecal injection, intracerebroventricular injection, inhalation, parenteral injection or infusion, oral, subcutaneous or intramuscular injection, buccal, transdermal, transmucosal, or topical. This includes application in vitro or in vivo, and includes animals (including humans) with one or more symptoms associated with Parkinson's disease.
The claims establish methods and compositions involving modified and sequence-specific antisense oligonucleotides targeting LRRK2 transcripts. They include chemical modification features, precise sequence requirements, exon targeting specificity, and routes of therapeutic administration.
Stated Advantages
Allows for modulation of LRRK2 splicing to eliminate mutations or reduce toxic LRRK2 protein levels associated with Parkinson’s disease.
Provides a therapeutic approach that can decrease full-length LRRK2 expression or generate isoforms with lower kinase activity.
Restores cellular phenotypes in models of Parkinson’s disease, including normalization of calcium homeostasis and neurite integrity.
Potentially ameliorates one or more symptoms associated with Parkinson’s disease by specifically targeting underlying genetic mutations.
Documented Applications
Treatment of Parkinson’s disease through administration of antisense oligonucleotides targeting LRRK2 transcripts.
Use in modulating splicing or expression of the LRRK2 transcript in vitro and in vivo, including in human and animal models.
Amelioration or prevention of symptoms associated with Parkinson’s disease by modulating LRRK2 splicing or expression.
Preparation of medicaments comprising antisense oligonucleotides for therapeutic use in Parkinson’s disease.
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