SCN2A regulatory compounds and methods

Abstract

To provide compounds and methods for modulating SCN2A. [Solution] The present invention provides compounds, methods, and pharmaceutical compositions that reduce the amount or activity of SCN2A RNA in cells or subjects, and in certain cases reduce the amount of SCN2A protein in cells or subjects. Such compounds, methods, and pharmaceutical compositions are useful for improving at least one symptom or feature of a disease or disorder related to voltage-gated sodium channel proteins, such as developmental and epileptic encephalopathy, intellectual disability, or autism spectrum disorder. Such symptoms and features include, but are not limited to, seizures, hypotonia, sensory integration disorders, delayed and impaired motor skills development, intellectual and cognitive impairment, motor and balance disorders, visual impairment, delayed language and speech, gastrointestinal disorders, delayed neurodevelopment, insomnia, and sudden, unexpected death in epilepsy.

Claims

1. A composition for use in improving seizures in a subject requiring improvement of seizures, comprising an oligomer compound, The aforementioned subjects have developmental and epileptic encephalopathy (DEE), The aforementioned oligomer compound 【Chemistry 43】 It contains a 6-10-4 MOE gapmer having the sequence (5' to 3') of (SEQ ID NO: 2510), Nucleosides 1-6 and 17-20, respectively (from 5' to 3'), are 2'-MOE nucleosides. Yes, each of nucleosides 7-16 is a 2'-β-D-deoxynucleoside. The internucleoside bonds between nucleosides 2-3, 3-4, 4-5, 5-6, 6-7 and 17-18 are phosphodiester internucleoside bonds, and between nucleosides 1-2, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 18-19 and 19-20 The nucleoside bond is a phosphorothioate nucleoside bond. A composition in which each cytosine is 5-methylcytosine.

2. The composition for use according to claim 1, wherein the seizure is any of a focal seizure, a clonic seizure, a tonic seizure, a generalized tonic-clonic seizure, a convulsive seizure, a myoclonic seizure, an absence seizure, or a blunt seizure.

3. The composition for use according to claim 1 or 2, wherein the seizures are frequent or prolonged.

4. The composition for use according to any one of claims 1 to 3, wherein the severity of seizures is reduced in the subject.

5. The composition for use according to any one of claims 1 to 4, wherein the frequency of seizures is reduced in the subject.

6. The composition for use according to any one of claims 1 to 5, wherein the subject has a disease or disorder related to SCN1A or SCN2A.

7. The composition for use according to claim 6, wherein the subject has a disease or disorder related to SCN2A.

8. The composition for use according to claim 7, wherein the disease or disorder associated with SCN2A is selected from the group consisting of early-onset seizure-induced epileptic encephalopathy (EE), late-onset seizure-induced epileptic encephalopathy, and benign familial neonatal-infant seizures.

9. The composition for use according to claim 7, wherein the disease or disorder associated with SCN2A is selected from the group consisting of Ohtahara syndrome, infantile epilepsy with migratory focal seizures, West syndrome, Lennon-Gastaut syndrome, Dravet syndrome, idiopathic / generic generalized epilepsy, lateral temporal lobe epilepsy, myoclonic astatic epilepsy, infantile migraine with partial seizures, and familial epileptic migraine.

10. The composition for use according to any one of claims 1 to 5, wherein the subject has a disease or disorder related to SCN1A.

11. The composition for use according to claim 10, wherein the disease or disorder associated with SCN1A is Dravet syndrome.

12. The oligomer compound is a modified oligonucleotide represented by the following chemical symbols 【Chemistry 44】 (Sequence ID 2510) Includes, During the ceremony, A = adenine nucleic acid base, m C = 5-methylcytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, e = 2'-MOE sugar moiety, d = 2'-β-D-deoxyribose sugar portion, s = phosphorothioate nucleoside interbonding, and A composition for use according to any one of claims 1 to 11, wherein o = phosphodiester nucleoside interbonding.

13. The oligomer compound is a modified oligonucleotide represented by the following chemical structure: 【Chemistry 45】 A composition for use according to claim 12, comprising (SEQ ID NO: 2510) or a salt thereof.

14. The composition for use according to claim 13, wherein the modified oligonucleotide is a sodium salt or a potassium salt.

15. The composition for use according to claim 14, wherein the modified oligonucleotide is a sodium salt.

16. The oligomer compound is a modified oligonucleotide represented by the following chemical structure: 【Chemistry 46】 A composition for use according to claim 12, comprising (SEQ ID NO: 2510).

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