Antisense compounds targeting apolipoprotein E receptor 2
Inventors
Rigo, Frank • Hastings, Michelle L.
Assignees
Rosalind Franklin University of Medicine and Science • Ionis Pharmaceuticals Inc
Publication Number
US-10472634-B2
Publication Date
2019-11-12
Expiration Date
2035-06-04
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Abstract
The present invention provides compounds comprising oligonucleotides complementary to an LRP8 transcript. Certain such compounds are useful for hybridizing to an LRP8 transcript, including but not limited, to an LRP8 transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the LRP8 transcript. In certain embodiments, such hybridization results in an increase in inclusion of exon 19 in the LRP8 mRNA transcript. In certain embodiments, such compounds are used to treat Alzheimer's Disease.
Core Innovation
The invention provides compounds comprising modified oligonucleotides that are complementary to a target region of an LRP8 transcript. These compounds can specifically hybridize to regions of the LRP8 transcript, including exon 19 or intronic sequences upstream or downstream of exon 19, allowing for targeted modulation of LRP8 transcript processing.
The problem addressed by the invention is the disruption of alternative splicing of the LRP8 transcript, particularly decreased inclusion of exon 19, which results in LRP8 protein isoforms lacking exon 19. Such forms act as dominant negative inhibitors and lead to defects in memory storage and spatial learning, processes that are critically impaired in diseases such as Alzheimer's Disease.
The core innovation centers on antisense compounds that, upon hybridization to specific regions of the LRP8 transcript, modulate its splicing. In certain embodiments, these antisense oligonucleotides increase the inclusion of exon 19 in the mature mRNA transcript, resulting in a higher ratio of LRP8 mRNA containing exon 19 compared to transcripts lacking exon 19. These compounds are further characterized by specific chemical modifications to improve functionality, stability, or affinity.
Certain embodiments of the invention demonstrate the use of these antisense compounds to treat or ameliorate symptoms of neurodegenerative diseases, particularly Alzheimer’s Disease, by restoring or enhancing exon 19 inclusion in LRP8 transcripts, thus restoring normal receptor signaling relevant to memory and learning.
Claims Coverage
The claims present five main inventive features, including specific antisense oligonucleotide compositions and methods of use directed at modulating LRP8 transcript splicing and related therapeutic interventions.
Modified oligonucleotides targeting LRP8 transcript
A compound comprising a modified oligonucleotide consisting of 8 to 30 linked nucleosides complementary to a target region of an LRP8 transcript. The modified oligonucleotide includes at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 3-30.
Optimized complementarity and targeting within LRP8 transcript
Further features specify the oligonucleotide as 100% complementary, or comprising at least 14, 15, 16, 17, or 18 contiguous nucleobases, to a target region within nucleobases 78901 to 79258 of SEQ ID NO.: 1. Additional features include nucleobase sequences comprising at least 10, 12, or 14 contiguous nucleobases of SEQ ID NOs: 3-30 and at least an 8 nucleobase portion of SEQ ID NOs: 17, 18, 19, or 20.
Chemical modifications to enhance oligonucleotide properties
Oligonucleotides further comprise at least one modified nucleoside. At least one modified nucleoside comprises a modified sugar moiety, which can be a 2′-substituted sugar moiety. The 2′-substituent may be selected from 2′-OMe, 2′-F, or 2′-MOE.
Method of modulating splicing of LRP8 transcript in cells
A method comprising contacting a cell with a compound defined above to modulate splicing of an LRP8 transcript.
Therapeutic methods using modified oligonucleotides
A method of increasing the inclusion of exon 19 in LRP8 mRNA by contacting a cell with the compound. A method of preventing, treating, ameliorating, or slowing the progression of a disease, disorder, or condition associated with neurodegeneration by administering the compound. A method of increasing the ratio of LRP8 mRNA having exon 19 relative to LRP8 mRNA without exon 19 by contacting a cell with the compound.
In summary, the claims cover compositions of chemically modified antisense oligonucleotides that are specifically complementary to regions of the LRP8 transcript, particularly for the purpose of modulating exon 19 splicing, as well as methods for their use in cells and for therapeutic intervention in neurodegenerative diseases.
Stated Advantages
The compounds can increase inclusion of exon 19 in LRP8 mRNA, which improves memory and/or learning by promoting production of active APOER2 isoforms.
Antisense oligonucleotides described can delay, ameliorate, prevent, or slow the progression of symptoms associated with neurodegenerative diseases, especially Alzheimer's Disease.
The modified oligonucleotides may have enhanced nuclease stability or increased binding affinity with the target nucleic acid relative to oligonucleotides comprising only nucleosides with naturally occurring sugar moieties.
Documented Applications
Use in the treatment, prevention, amelioration, or slowing of progression of diseases, disorders, or conditions associated with neurodegeneration, including Alzheimer's Disease and Down Syndrome.
Use for increasing the inclusion of exon 19 in LRP8 mRNA or protein in cells in vitro or in animals.
Preparation of medicaments for use in the treatment or amelioration of one or more symptoms of Alzheimer's Disease.
Use as research tools for modulating splicing of the LRP8 transcript in cells.
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