WO2019183536A1 – September 26, 2019 – MODULATION OF NEURONAL NKCC1 AS A THERAPEUTIC STRATEGY FOR SPASTICITY AND RELATED DISORDERS

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Inventors :

AHMED, Zaghloul - 136 Ada Drive, Staten Island, New York 10314

Owner :

RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK

Application Number :

WOUS19023675

Document Number :

WO2019183536A1

Priority Date :

March 22, 2018

Filing Date :

March 22, 2019

Date of Grant/ Publication :

September 26, 2019

Class :

A61K31 / 18; A61K31 / 433; A61K38 / 48; C07K14 / 33; A61P25 / 14; A61P21 / 00; A61P25 / 00

Abstract

Methods and systems for treating spasticity, hypertonia or dystonia are disclosed.

Claim(s)

1. A method of treating spasticity, hypertonia or dystonia comprising the step of administering a therapeutically effective amount of at least one agent that inhibits NKCC1 biological activity or at least one agent that decreases NKCC1 gene expression levels and/or protein expression levels.;
11. A method of treating a disorder in a vertebrate being, comprising the steps of: applying direct current stimulation between a first electrode and a second electrode of a direct current source with the first electrode being at or proximate to a dorsal aspect of a spinal cord of a vertebrate being or with the first electrode being on a cranium of a vertebrate being; and applying the direct current stimulation at an intensity and for a period of time sufficient to change biological activity of or level of gene expression and/or protein expression of NKCC1; wherein the second electrode is placed at a position remote from the first electrode and the first and second electrodes are oppositely charged, and wherein the direct current is at least one of constant, continuous, pulsed, intermittent, varying and non-varying.;
12. A method of treating a disorder in a vertebrate being, comprising the steps of: applying a first direct current stimulation between a first electrode and a second electrode of a direct current source with the first electrode being at or proximate to a dorsal aspect of a spinal cord of a vertebrate being; applying a second direct current stimulation between a third electrode and a fourth electrode of a direct current source with the third electrode being at or proximate to a peripheral nerve of a vertebrate being; and applying the direct current stimulation at an intensity and for a period of time sufficient to change biological activity of or level of gene expression and/or protein expression of NKCC1; wherein the second electrode is placed at a position remote from the first electrode and the first and second electrodes are oppositely charged, and the fourth electrode is placed at a position remote from the third electrode and the third and fourth electrodes are oppositely charged, and wherein the direct current is at least one of constant, continuous, pulsed, intermittent, varying and non-varying.;
37. A system for treatment of spasticity, hypertonia or dystonia in a vertebrate being, the system comprising: a first stimulation component configured to provide peripheral direct current stimulation of a peripheral nerve associated with spasticity, hypertonia or dystonia in a vertebrate being; said first stimulation component including a neural stimulation circuit having neural stimulation poles configured to stimulate said peripheral nerve; a second stimulation component configured to provide spinal direct current stimulation at a spinal location associated with regulation of said peripheral nerve, said second stimulation component defining a spinal stimulation circuit having an active spinal stimulation pole and a spinal reference pole, said spinal stimulation circuit configured to provide trans-spinal direct current stimulation between said spinal stimulation pole and said spinal reference pole for stimulating said spinal location; the active spinal stimulation pole being relatively proximal to said spinal location; the spinal reference pole being relatively distal to said spinal location; and a controller component configured to ensure that said active spinal pole and said proximal neural pole are excited at opposite polarities, forming a resulting polarization circuit, said resulting polarization circuit being configured to provide a polarizing current flow between said active spinal pole and said proximal neural pole according to said opposite polarities, for changing biological activity of or level of gene expression and/or protein expression of a target molecule according to said polarizing current flow; said controller component being also configured to provide peripheral direct current stimulation and spinal direct current stimulation for a predetermined time period and repeat stimulation a predetermined number of times over a predetermined number of days.;
46. A stimulation device for regulating biological activity associated with one of the spinal cord, the brain or a peripheral nerve, comprising: a direct current voltage source having a plurality of terminals; a first of the terminals for connecting a first electrode to the direct current voltage source; the first electrode being at or proximate to a dorsal aspect of a spinal cord of a vertebrate being, on a cranium of a vertebrate being or at or proximal to a peripheral nerve of a vertebrate being; a second of the terminals for connecting a second electrode to the direct current voltage source; the second electrode being placed at a position remote from the first electrode; the first and second electrodes being oppositely charged and configured to form a current path for stimulating said spinal cord, said cranium or said peripheral nerve; and a controller component configured to control of current flow between the electrodes across said current path; the controller component being also configured to provide said direct current flow for stimulation of said current path across said spinal cord, across said cranium or across said peripheral nerve for a predetermined time period and repeat stimulation a predetermined number of times over a predetermined number of days.;
52. A method of treating ALS in a vertebrate being, comprising the steps of: applying stimulation between an A electrode and a ? electrode of a direct current source with the A electrode being at or proximate to a first location of a dorsal aspect of a spinal cord of a vertebrate being or with the A electrode being at a first location on a cranium of a vertebrate being; and applying the direct current stimulation at an intensity and for a period of time sufficient to prolong neuronal cell life; wherein the ? electrode is placed at a first position remote from the A electrode and the A and ? electrodes are oppositely charged, and wherein the direct current is at least one of constant, continuous, pulsed, intermittent, varying and non-varying.;
58. A method of treating ALS in a vertebrate being, comprising the steps of: applying a first stimulation between an A electrode and a ? electrode of a direct current source with the A electrode being at or proximate to a first location of a dorsal aspect of a spinal cord of a vertebrate being; applying a second stimulation between a C electrode and a D electrode of a direct current source with the C electrode being at a first location on a cranium of a vertebrate being; and applying the direct current stimulation at an intensity and for a period of time sufficient to prolong neuronal cell life; wherein the ? electrode is placed at a position remote from the A electrode and the A and ? electrodes are oppositely charged, and the D electrode is placed at a position remote from the C electrode and the C and D electrodes are oppositely charged, and wherein the direct current is at least one of constant, continuous, pulsed, intermittent, varying and non-varying.;
92. A system for treatment of ALS in a vertebrate being, the system comprising: a plurality of A stimulation components configured to provide peripheral direct current stimulation of a peripheral nerve at a plurality of locations along the peripheral nerve or to provide peripheral direct current stimulation of a plurality of peripheral nerves in a vertebrate being; each of said A stimulation components including a neural stimulation circuit having neural stimulation poles configured to stimulate said peripheral nerve or plurality of peripheral nerves; a plurality of ? stimulation components configured to provide spinal direct current stimulation at a plurality of spinal locations associated with regulation of said peripheral nerve or plurality of peripheral nerves, each of said ? stimulation components defining a spinal stimulation circuit having an active spinal stimulation pole and a spinal reference pole, said spinal stimulation circuit configured to provide trans-spinal direct current stimulation between said spinal stimulation pole and said spinal reference pole for stimulating said spinal location; the active spinal stimulation pole being relatively proximal to said spinal location; the spinal reference pole being relatively distal to said spinal location; and a controller component configured to ensure that said active spinal pole and said proximal neural pole are excited at opposite polarities, forming a resulting polarization circuit, said resulting polarization circuit being configured to provide a polarizing current flow between said active spinal pole and said proximal neural pole according to said opposite polarities, for changing biological activity of or level of gene expression and/or protein expression of a target molecule according to said polarizing current flow; said controller component being also configured to provide peripheral direct current stimulation and spinal direct current stimulation for a predetermined time period and repeat stimulation a predetermined number of times over a predetermined number of days.;
claim 9: 101. A stimulation device for treatment of ALS, comprising: a direct current voltage source having a plurality of terminals; a plurality of A terminals for connecting a plurality of A electrodes to the direct current voltage source; the plurality of A electrodes being at a plurality of locations of a dorsal aspect of a spinal cord of a vertebrate being or at a plurality of locations on a cranium of a vertebrate being a plurality of ? terminals for connecting a plurality of ? electrodes to the direct current voltage source; the plurality of ? electrodes being placed positions remote from the plurality of A electrodes; the A and ? electrodes being oppositely charged; and a controller component configured to control of current flow between the electrodes; the controller component being also configured to provide direct current stimulation for a predetermined time period and repeat stimulation a predetermined number of times over a predetermined number of days.;
claim 10: 107. An agent that inhibits NKCC1 biological activity or an agent that decreases NKCC1 gene expression levels and/or protein expression levels for use in treating spasticity, hypertonia or dystonia.

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