Compounds and methods for the modulation of amyloid-β precursor protein
Inventors
Rigo, Frank • Hastings, Michelle L.
Assignees
Rosalind Franklin University of Medicine and Science • Ionis Pharmaceuticals Inc
Publication Number
US-11732260-B2
Publication Date
2023-08-22
Expiration Date
2039-03-01
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Abstract
Certain embodiments disclosed herein are directed to compounds and methods for modulating APP expression. In certain embodiments, modulating the splicing of amyloid precursor protein (APP) reduces amyloid β (Aβ) production.
Core Innovation
The invention is directed to compounds and methods for modulating amyloid precursor protein (APP) expression by targeting the splicing process of the APP transcript. Specifically, modified oligonucleotides are designed to hybridize to APP pre-mRNA and modulate its splicing in such a way that it prevents the formation of amyloid β (Aβ), particularly the neurotoxic Aβ42 form. The compounds include modified oligonucleotides with particular chemical modifications such as modified sugar moieties and internucleoside linkages.
The problem being addressed is the accumulation of Aβ peptide in the brain, which forms extracellular plaques—a pathological hallmark of Alzheimer's Disease. Aβ is generated by proteolytic cleavage of APP, and certain forms like Aβ42 are especially prone to aggregation and neurotoxicity. Reducing Aβ or specifically Aβ42 production is therefore a major therapeutic goal to delay or prevent Alzheimer's Disease progression.
The disclosed invention provides modified oligonucleotides that target exon 17 of the APP transcript to block its splicing. When exon 17 splicing is blocked, an alternatively spliced APP mRNA is produced that lacks 49 amino acids, including the γ-secretase cleavage sites responsible for generating toxic forms of Aβ. These oligonucleotides consequently reduce inclusion of exon 17, inhibit the production of Aβ and Aβ42, and can be used for therapeutic, diagnostic, and research purposes involving APP and Aβ modulation.
Claims Coverage
The patent contains two independent claims that establish the inventive features of the modified oligonucleotides targeting APP splicing.
Modified oligonucleotide targeting APP transcript exon 17 region
A modified oligonucleotide consisting of 16 to 19 linked nucleosides, with a nucleobase sequence that is 100% complementary to an equal-length portion within nucleobase 282128 and nucleobase 282150 of SEQ ID NO: 1. The oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
Modified oligonucleotides with defined sequences and chemical modifications
A modified oligonucleotide consisting of 18 to 21 linked nucleosides, where the nucleobase sequence is selected from SEQ ID NOs: 7-10, 13, 14, 16, 19-21, 23, 24, 27, 28, 30-32, and 34-42, and the oligonucleotide includes at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
The inventive features focus on specific, chemically modified oligonucleotides designed to modulate APP splicing by targeting a defined exon region, using defined sequences and chemical modifications to achieve the desired biological effect.
Stated Advantages
Modified oligonucleotides disclosed herein can reduce the inclusion of exon 17 in APP mRNA, thereby reducing the amount of Aβ and specifically Aβ42.
Blocking exon 17 splicing induces an alternatively spliced APP mRNA isoform lacking 49 amino acids, including γ-secretase cleavage sites, thus preventing formation of toxic Alzheimer's Disease associated Aβ.
Reducing Aβ or Aβ42 production or preventing their formation from APP can delay or prevent the formation of senile plaques caused by aggregation of Aβ or Aβ42.
Documented Applications
Modulation of splicing of the APP transcript in cells to reduce inclusion of exon 17 and thus affect Aβ and Aβ42 production.
Reducing expression or preventing the formation of amyloid β (Aβ) and specifically Aβ42 in human and animal cells.
Use in human cells, Down's Syndrome fibroblast cell lines, and animal (mouse) models to alter APP splicing and subsequently decrease Aβ42 secretion and plaque formation.
Use in pharmaceutical compositions for administration to animals, including humans, via oral, rectal, transmucosal, enteral, topical, suppository, inhalational, intrathecal, intracerebroventricular, intraperitoneal, intranasal, intraocular, intratumoral, and parenteral routes.
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