Treatment of neurological and neurodevelopmental diseases and disorders associated with aberrant ion channel expression and activity
Provided are methods for treating and/or reducing the symptoms of a neurological or neurodevelopmental disease or disorder characterized by ectopic expression of certain ion channels, in particular, the Nav1.8 subtype SCN10a sodium channel, or the KCNQ1 potassium channel, in neuronal cells of the central nervous system (CNS) of a subject by administering to a subject in need an antagonist of one or both of these ion channels, and in particular, an antagonist of SCN10a, to block, reduce, or suppress the aberrant CNS neuronal ion channel expression and/or activity and normalize behavioral and cognitive defects associated with the neurological and neurodevelopmental disease or disorder, so as to treat and/or reduce the symptoms of the neurological or neurodevelopmental disease or disorder. Examples of such diseases or disorders that may be treated by the described methods include, for example, Pitt-Hopkins Syndrome (PTHS), autism, autism spectrum disorder, schizophrenia, 18q syndrome and the like.
1. A method of reducing at least one symptom of Pitt-Hopkins Syndrome (PTHS), said method comprising: administering to the subject a therapeutically effective amount of a SCN10a selective antagonist or a KCNQ1 selective antagonist or a combination of thereof to treat the disease or disorder, wherein the SCN10a selective antagonist is selected from the group consisting of A-803467, PF-01247324, PF-04885614, PF-04531083, PF-5157147, A-887826, ambroxol hydrochloride, APETX2, vinpocetine, PF-6305591, DSP-2230, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, VX-150, aryl-substituted nicotinamide derivatives of A-803467, PF-01247324, PF-04531083, PF-6305591, PF-04885614, PF-5157147, A-887826, Ambroxol hydrochloride, DSP-2230, vinpocetine, VX-150, or APETX2, and a salt or hydrate and wherein the KCNQ1 selective antagonist is selected from the group consisting of Chromanol 293B, MIR-1556, UCL2077, JNJ303, L-735821 (L-7), fenofibrate; and a salt or hydrate thereof.
2. The method according to claim 1 , wherein the subject is administered a therapeutically effective amount of a SCN10a selective antagonist.
3. The method according to claim 2 , wherein the SCN10a antagonist is PF-04531083.
4. The method according to claim 1 , wherein the subject is administered a therapeutically effective amount of a SCN10a selective antagonist in combination with a therapeutically effective amount of a KCNQ1 antagonist.
5. The method according to claim 1 , wherein the subject is administered a therapeutically effective amount of a KCNQ1 selective antagonist.
6. A method of reducing an aberrant excitability phenotype of CNS neuronal cells expressing SCN10a or KCNQ1 in a subject having a neurological or neurodevelopmental disorder associated with abnormal TCF4 expression and/or function and selected from Pitt-Hopkins Syndrome (PTHS), autism, autism spectrum disorder, 18q syndrome and schizophrenia, the method comprising administering to the subject a therapeutically effective amount of a selective antagonist of SCN10a or KCNQ1 to reduce the symptoms of the neurological or neurodevelopmental disorder in the subject, wherein the SCN10a selective antagonist is selected from the group consisting of A-803467, PF-01247324, PF-04885614, PF-04531083, PF-5157147, A-887826, ambroxol hydrochloride, APETX2, vinpocetine, PF-6305591, DSP-2230, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, VX-150, aryl-substituted nicotinamide derivatives of A-803467, PF-01247324, PF-04531083, PF-6305591, PF-04885614, PF-5157147, A-887826, Ambroxol hydrochloride, DSP-2230, vinpocetine, VX-150, or APETX2, and a salt or hydrate and wherein the KCNQ1 selective antagonist is selected from the group consisting of Chromanol 293B, MIR-1556, UCL2077, JNJ303, L-735821 (L-7), fenofibrate; and a salt or hydrate thereof.
7. The method according to claim 6 , wherein the selective antagonist is SCN10a and the SCN10a antagonist is PF-04531083.
8. The method according to claim 6 , wherein the neurological or neurodevelopmental disease or disorder is PTHS.
9. The method according to claim 6 , wherein the neurological or neurodevelopmental disease or disorder is 18q syndrome.
10. The method according to claim 6 , wherein the neurological or neurodevelopmental disease or disorder is schizophrenia.
11. The method according to claim 6 , wherein the subject is administered a therapeutically effective amount of a SCN10a selective antagonist.
12. The method according to claim 11 , wherein the SCN10a antagonist is PF-04531083.
13. The method according to claim 6 , wherein the subject is administered a therapeutically effective amount of a KCNQ1 selective antagonist.
14. A method of inhibiting the activity of Na v 1.8 sodium channels or KCNQ1 potassium channels in a subject having a neurological or neurodevelopmental disorder associated with abnormal TCF4 expression and/or function and selected from Pitt-Hopkins Syndrome (PTHS), autism, autism spectrum disorder, 18q syndrome, and schizophrenia, the method comprising administering to the subject a therapeutically effective amount of a selective antagonist of SCN10a or KCNQ1 to reduce the symptoms of the neurological or neurodevelopmental disorder in the subject, wherein the SCN10a selective antagonist is selected from the group consisting of A-803467, PF-01247324, PF-04885614, PF-04531083, PF-5157147, A-887826, ambroxol hydrochloride, APETX2, vinpocetine, PF-6305591, DSP-2230, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, VX-150, aryl-substituted nicotinamide derivatives of A-803467, PF-01247324, PF-04531083, PF-6305591, PF-04885614, PF-5157147, A-887826, Ambroxol hydrochloride, DSP-2230, vinpocetine, VX-150, or APETX2, and a salt or hydrate and wherein the KCNQ1 selective antagonist is selected from the group consisting of Chromanol 293B, MIR-1556, UCL2077, JNJ303, L-735821 (L-7), fenofibrate; and a salt or hydrate thereof.
15. The method according to claim 14 , wherein the neurological or neurodevelopmental disease or disorder is PTHS.
16. The method according to claim 14 , wherein the neurological or neurodevelopmental disease or disorder is 18q syndrome.
17. The method according to claim 14 , wherein the neurological or neurodevelopmental disease or disorder is schizophrenia.
18. The method according to claim 14 , wherein the neurological or neurodevelopmental disease or disorder is autism or autism spectrum disorder.
19. The method according to claim 14 , wherein the subject is administered a therapeutically effective amount of a SCN10a selective antagonist.
20. The method according to claim 14 , wherein the subject is administered a therapeutically effective amount of a KCNQ1 selective antagonist.