Compounds and methods for modulating GFAP

Patent metadata

Field	Value
Publication number	US-12502402-B2
Application number	US-202318243156-A
Country	US
Kind code	B2
Filing date	Sep 7, 2023
Priority date	Jul 26, 2019
Publication date	Dec 23, 2025
Grant date	Dec 23, 2025

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of GFAP RNA in a cell or subject, and in certain instances reducing the amount of GFAP in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a leukodystrophy. Such symptoms and hallmarks include motor delays, cognitive delays, paroxysmal deterioration, seizures, vomiting, swallowing difficulties, ataxic gait, palatal myoclonus, autonomic dysfunction, and presence of intra-astrocytic inclusions called Rosenthal fibers. Such leukodystrophies include Alexander Disease.

First claim

The invention claimed is:

1 . A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

2 . A modified oligonucleotide according to the following chemical structure:

3 . The modified oligonucleotide of claim 1 , which is the sodium salt or the potassium salt.

4 . A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent.

5 . The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate-buffered saline (PBS).

6 . The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition consists of the modified oligonucleotide and artificial cerebrospinal fluid.

7 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
m C es A eo m C eo A eo T eo T eo m C ds A ds m C ds T ds A ds A ds T ds A ds T ds T ds T eo A es A es m C e (SEQ ID NO: 21), wherein:
A=an adenine nucleobase, m C=a 5-methylcytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.

8 . The oligomeric compound of claim 7 , comprising the modified oligonucleotide covalently linked to a conjugate group.

9 . A pharmaceutical composition comprising the oligomeric compound of claim 7 , and a pharmaceutically acceptable diluent.

10 . The pharmaceutical composition of claim 9 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

11 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition consists of the oligomeric compound and artificial cerebrospinal fluid.

12 . A method comprising administering to an individual the pharmaceutical composition of claim 4 .

13 . A method of treating Alexander disease, comprising administering to an individual having or at risk of having Alexander disease a therapeutically effective amount of the pharmaceutical composition according to claim 4 , thereby treating Alexander disease.

14 . The method of claim 13 , wherein at least one symptom or hallmark of Alexander disease is ameliorated.

15 . The method of claim 14 , wherein at least one symptom or hallmark is any of motor delays, cognitive delays, paroxysmal deterioration, seizures, vomiting, swallowing difficulties, ataxic gait, palatal myoclonus, autonomic dysfunction, or the presence of intra-astrocytic inclusions called Rosenthal fibers.

16 . The method of claim 13 , wherein the pharmaceutical composition is administered to the central nervous system or systemically.

17 . The method of claim 13 , wherein the pharmaceutical composition is administered to the central nervous system and systemically.

18 . The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

19 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial cerebrospinal fluid.

20 . The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

21 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and PBS.

22 . A pharmaceutical composition comprising the modified oligonucleotide of claim 2 and a pharmaceutically acceptable diluent.

23 . The pharmaceutical composition of claim 22 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

24 . The pharmaceutical composition of claim 23 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

25 . The pharmaceutical composition of claim 23 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

26 . A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent.

27 . The pharmaceutical composition of claim 26 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

28 . The pharmaceutical composition of claim 27 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

29 . The pharmaceutical composition of claim 27 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

30 . A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

31 . A population of modified oligonucleotides of claim 2 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

32 . A population of modified oligonucleotides of claim 3 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

33 . A population of oligomeric compounds of claim 7 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

34 . A pharmaceutical composition comprising the population of modified oligonucleotides of claim 30 and a pharmaceutically acceptable diluent.

35 . The pharmaceutical composition of claim 34 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

36 . A pharmaceutical composition comprising the population of modified oligonucleotides of claim 31 and a pharmaceutically acceptable diluent.

37 . The pharmaceutical composition of claim 36 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

38 . A pharmaceutical composition comprising the population of modified oligonucleotides of claim 32 and a pharmaceutically acceptable diluent.

39 . The pharmaceutical composition of claim 38 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

40 . A pharmaceutical composition comprising the population of oligomeric compounds of claim 33 and a pharmaceutically acceptable diluent.

41 . The pharmaceutical composition of claim 40 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or PBS.

42 . The method of claim 12 , wherein the individual has or is at risk of having Alexander disease.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Powers Berit Elissa
• Rigo Frank

Classifications

• C12N2310/341

  Gapmers, i.e. of the type ===---=== · CPC title

• C07H21/02

  with ribosyl as saccharide radical · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title