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US-20260124232-A1 - RUNX1 MODULATORS

US20260124232A1US 20260124232 A1US20260124232 A1US 20260124232A1US-20260124232-A1

Abstract

Provided herein are compounds, compositions, and methods for lowering expression levels of runt-related transcription factor 1 (RUNX1) in a cell, tissue or animal. Further provided are methods of improving memory and cognitive functioning in individuals with Down syndrome (DS) using an antisense compound targeted to a RUNX1 nucleic acid. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders. Further provided are methods of decreasing inflammation and slowing cognitive decline in individuals with dementia.

Inventors

  • Carter PALMER
  • Christine S. LIU
  • Linnea RANSOM
  • Nyssa WILLIAMS
  • Jerold Chun

Assignees

  • Sanford Burnham Prebys Medical Discovery Institute

Dates

Publication Date
20260507
Application Date
20250911

Claims (20)

  1. 1 . An oligomeric compound, or a salt thereof, comprising a modified oligonucleotide consisting of 10-30 linked nucleosides wherein the modified oligonucleotide is at least 90% complementary to any of the nucleobase sequences of SEQ ID NO: 1-19, when measured across the entire nucleobase sequence of the modified oligonucleotide, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage.
  2. 2 . An oligomeric compound, or a salt thereof, comprising a modified oligonucleotide consisting of 10-30 linked nucleosides wherein the modified oligonucleotide has a nucleobase sequence that is targeted to any of the nucleobase sequences of SEQ ID NO: 39-57, when measured across the entire nucleobase sequence of the modified oligonucleotide, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage.
  3. 3 . The oligomeric compound of claim 2 , wherein the modified oligonucleotide comprises at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 modifications, or number of modifications within a range defined by any of the preceding numbers, selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage.
  4. 4 . The oligomeric compound of claim 2 , wherein the modified oligonucleotide is at least 90% complementary to any of the nucleobase sequences of SEQ ID NO: 39-57.
  5. 5 . The oligomeric compound of claim 2 , wherein the modified oligonucleotide is 100% complementary to any of the nucleobase sequences of SEQ ID NO: 39-57.
  6. 6 . An oligomeric compound (formula ASO (15)) according to the following formula: or a salt thereof, wherein: each R 1 is independently selected from the group consisting of OH and SH; each R 2 is independently selected from the group consisting of hydrogen, halo, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CH 2 OCH 3 , and OCH 2 CF 3 ; each R 3 is independently selected from the group consisting of hydrogen, halo, OH, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CH 2 OCH 3 , and OCH 2 CF 3 ; and each R 4 is independently selected from the group consisting of hydrogen and CH 3 .
  7. 7 . The compound of claim 6 , wherein R 3 is hydrogen.
  8. 8 . The compound of claim 6 , wherein each R 2 is OCH 2 CH 3 or OCH 3 .
  9. 9 . The compound of claim 6 , wherein each R 2 is OCH 2 CH 2 OCH 3 .
  10. 10 . The compound of claim 6 , wherein each R 1 is SH.
  11. 11 . A pharmaceutical composition comprising an oligomeric compound of claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent.
  12. 12 . A method of improving cognitive function in a subject in need thereof, comprising administering a compound of claim 1 , or a salt thereof to the subject.
  13. 13 . The method of claim 12 , wherein the subject has an overexpression of RUNX1.
  14. 14 . The method of claim 12 , wherein the subject has Down syndrome.
  15. 15 . The method of claim 12 , wherein the subject has Alzheimer's disease.
  16. 16 . A method of treating a disease associated with RUNX1 in a subject in need thereof, comprising administering a compound of claim 1 , or a salt thereof to the subject.
  17. 17 . A method of treating cognitive loss associated with a neurodegenerative disease or disorder, the method comprising: identifying a subject in need of treatment for cognitive decline; and administering a therapeutically effective amount of a RUNX1 inhibitor to the subject thereby reducing the expression of RUNX1 in microglia of the subject and treating the cognitive loss in the subject.
  18. 18 . The method of claim 17 , wherein the subject is diagnosed with a neurodegenerative disease or disorder, wherein the neurodegenerative disease or disorder comprises Alzheimer's disease, Parkinson's disease, Down syndrome, Down syndrome associated dementia, prion disease, Amyotrophic lateral sclerosis, Nasu Hakola disorder, spinal muscular atrophy, or spinocerebellar ataxia.
  19. 19 . The method of claim 18 , wherein the neurodegenerative disease or disorder is Down syndrome or Down syndrome associated dementia.
  20. 20 . The method of claim 18 , wherein the neurodegenerative disease or disorder is Alzheimer's disease.

Description

CROSS REFERENCE This application is a continuation of International Application No. PCT/US2024/019997, filed Mar. 14, 2024, and claims the benefit of U.S. Provisional Application No. 63/490,685, filed Mar. 16, 2023, all of which are incorporated by reference in their entirety herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under R56 AG073965 awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, generated on Mar. 13, 2024, is named 42256-615 301_SL.XML and is 92,074 bytes in size. BACKGROUND RUNX1 is a transcription factor expressed in immune cells throughout the body. Within the central nervous system (CNS) it is expressed in microglia, the “resident immune cells” of the brain. Microglia have numerous functions and states. They are classically noted for modulating inflammation and are now recognized to have a multitude of diverse functions including synaptic maintenance, memory removal, CNS surveillance, aggregate formation, and others. It has been shown that individuals with Down syndrome (DS) have abnormal microglia, and that these are characterized by significant overexpression of RUNX1, a gene that lies on human chromosome 21. Additionally, it has been shown that RUNX1 overexpression is associated with the rare primary microgliopathy Nasu Hakola Disorder as well as microglia in Alzheimer's disease. RUNX1 expression in microglia increases with the development of Alzheimer's disease and has been identified to regulate disease pathways in microglia in neurodegeneration. Decreasing RUNX1 levels induces microglia turnover and appears to return microglia to a more homeostatic state, decreasing neuroinflammation as a result. There is currently a lack of effective therapeutics to decrease neuroinflammation in numerous neurodegenerative diseases, including Down syndrome associated dementia, Alzheimer's disease in the general population, and Nasu Hakola disorder. BRIEF SUMMARY OF THE INVENTION Provided herein are methods to decrease RUNX1 levels to control microglial functional states. More specifically, the present application discloses the ability to decrease RUNX1 levels using antisense oligonucleotides (ASOs). Decreasing RUNX1 levels can modify transcriptomic, morphological, and functional aspects of microglia and may, for example, normalize the microglia in Down syndrome brains, Alzheimer's disease, and generally inflamed brains, in turn improving memory and potentially additional cognitive attributes for these individuals. One embodiment provides an oligomeric compound or a salt thereof, comprising a modified oligonucleotide consisting of 10-30 linked nucleosides wherein the modified oligonucleotide has a nucleobase sequence that is at least 80% complementary to any of the nucleobase sequences of SEQ ID NO:1-19 when measured across the entire nucleobase sequence of the modified oligonucleotide, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage. One embodiment provides an oligomeric compound, or a salt thereof, comprising a modified oligonucleotide consisting of 10-30 linked nucleosides wherein the modified oligonucleotide has a nucleobase sequence that is targeted to any of the nucleobase sequences of SEQ ID NO: 39-57, when measured across the entire nucleobase sequence of the modified oligonucleotide, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage. One embodiment provides an oligomeric compound (formula ASO (1)) according to the following formula: or a salt thereof, wherein:each R1 is independently selected from the group consisting of OH and SH;each R2 is independently selected from the group consisting of hydrogen, halo, OCH3, OCF3, OCH2CH3, OCH2CH2OCH3, and OCH2CF3;each R3 is independently selected from the group consisting of hydrogen, halo, OH, OCH3, OCF3, OCH2CH3, OCH2CH2OCH3, and OCH2CF3; andeach R4 is independently selected from the group consisting of hydrogen and CH3. In some embodiments, R4 is hydrogen. In some embodiments, R4 is CH3. One embodiment provides an oligomeric compound (formula ASO (2)) according to the following formula: or a salt thereof, wherein:each R1 is independently selected from the group consisting of OH and SH;each R2 is independently selected from the group consisting of hydrogen, halo, OCH3, OCF3, OCH2CH3, OCH2CH2OCH3, and OCH2CF3;each R3 is independently selected from the group consisting of hydrogen, halo, OH, OCH3, OCF3, OCH2CH3, OCH2CH2OC3, and OCH2CF3; andeach R4 is independently selected from the group consisting of hydrogen and