Compounds and methods for reducing prion expression
Inventors
Freier, Susan M. • Bui, Huynh-Hoa • Zhao, Hien Thuy
Assignees
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Publication Number
US-12281305-B2
Publication Date
2025-04-22
Expiration Date
Abstract
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PRNP RNA in a cell or animal, and in certain instances reducing the amount of PrP protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks spongiform changes in the brain, development of abnormal protein aggregates, neuronal loss, markers of neuronal loss, rapidly progressing dementia, and death. Such neurodegenerative diseases include prion diseases, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), familial Creutzfeldt-Jakob Disease (fCJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru, Alzheimer's disease, or Parkinson's disease.
Core Innovation
The invention relates to modified oligonucleotides targeting human PRNP RNA, including PRNP-complementary gapmer chemistries, oligomeric antisense oligonucleotides, and MOE gapmer modified oligonucleotides. The disclosed compounds are defined by specific chemical structures or chemical notation, including nucleobases A, mC, G, and T; 2′-MOE modified sugar and 2′-β-D deoxyribosyl sugar motifs; and phosphorothioate and phosphodiester internucleoside linkages, with embodiments identified by SEQ ID and compound numbers.
The gapmers include central gap segments and wing segments, with defined 2′-MOE wings and a deoxy gap segment, and optionally cEt or 2′-OMe substitutions. The invention also includes populations that are chirally enriched or stereorandom, including stereorandom phosphorothioate internucleoside linkages throughout, and mixed backbone arrangements with phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.
The disclosed oligonucleotides reduce human PRNP RNA and PrP protein, including PrP^C and PrP^Sc, and are associated with amelioration of neurodegenerative disease hallmarks. The document links the activity to rapidly progressing dementia and death and describes spongiform changes in brain, abnormal protein aggregates, and neuronal loss as hallmarks associated with the claimed activity.
Claims Coverage
The independent claims identified across the inputs cover modified oligonucleotides or compounds defined by chemical structure or chemical notation, together with related pharmaceutical compositions. The consolidated claim scope includes six inventive features centered on PRNP-targeting modified oligonucleotide structures, salts, stereochemical population constraints, and compositions using artificial cerebrospinal fluid as a diluent.
Modified oligonucleotide defined by a chemical structure
A modified oligonucleotide according to a specified chemical structure, or a salt thereof.
Modified oligonucleotide defined by a chemical structure with stereorandom phosphorothioate population
A modified oligonucleotide according to a specified chemical structure, wherein a population is characterized by having stereorandom phosphorothioate internucleoside linkages throughout.
Modified oligonucleotide specified by chemical notation with defined nucleobases, sugars, linkages and SEQ ID NO
A compound comprising a modified oligonucleotide according to chemical notation including A, mC, G, and T nucleobases, a 2′-MOE modified sugar, a 2′-β-D deoxyribosyl sugar, phosphorothioate and phosphodiester internucleoside linkages, and SEQ ID NO: 2302.
Pharmaceutical composition using artificial cerebrospinal fluid diluent
A pharmaceutical composition including the modified oligonucleotide together with a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.
Population with stereorandom phosphorothioate internucleoside linkages
A population of modified oligonucleotides or compounds in which all phosphorothioate internucleoside linkages are stereorandom.
Pharmaceutical composition consisting essentially of modified oligonucleotide and artificial cerebrospinal fluid
A pharmaceutical composition that consists essentially of a modified oligonucleotide and artificial cerebrospinal fluid, or consists essentially of a population of modified oligonucleotides or compounds and artificial cerebrospinal fluid.
The claims focus on modified oligonucleotides defined by structure or notation, including salts and SEQ ID NO-based definitions, together with population-level stereochemical constraints and pharmaceutical compositions formulated with artificial cerebrospinal fluid. The claim scope repeatedly emphasizes phosphorothioate linkage stereochemistry and narrowed composition language.
Stated Advantages
Reduces PRNP RNA, including reduction in spinal cord and cortex.
Reduces PrP protein including PrP^C and PrP^Sc.
Reduced human PRNP RNA after intracerebroventricular or intrathecal dosing, with PRNP RNA reported relative to a PBS negative control.
Treating or ameliorating neurodegenerative disease symptoms or hallmarks, including spongiform changes, abnormal protein aggregates, neuronal loss, rapidly progressing dementia, and death.
Behavioral tolerability characterized using functional observational battery scores and adverse event onset.
Documented Applications
Use of PRNP-complementary modified oligonucleotides in human PRNP knock-in mice via intracerebroventricular and intrathecal dosing, with PRNP RNA reduction measured by RTPCR.
Treating or ameliorating neurodegenerative disease symptoms or hallmarks associated with prion diseases by reducing PRNP RNA and, in some embodiments, reducing prion protein (PrP).
Intrathecal administration and reduction of PrP in cerebrospinal fluid.
Pharmaceutical composition use with artificial cerebrospinal fluid as a diluent, including formulations described as consists essentially of, and administration routes including oral administration, buccal administration, intrathecal, and intracerebroventricular.
PRNP RNA knockdown in vitro and in vivo for compounds complementary to PRNP RNA hotspot regions, including reduction of PRNP RNA expression in spinal cord and cortex.
In vivo comparative evaluation of tolerability using functional observational battery scores and adverse event onset.
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