# US 9,517,223 B2 · Methods to treat neurodegenerative diseases

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,517,223 B2
- Document ID: US9517223B2
- Status: Granted
- Kind: B2
- Application number: 14/420,245
- Filed: 2013-08-06
- Published: 2015-07-09
- Granted: 2016-12-13
- Earliest claimed: 2012-08-07
- Assignees: The General Hospital Corporation; Children's Medical Center Corporation; President and Fellows of Harvard College
- Applicants: Children's Medical Center Corporation; President and Fellows of Harvard College; The General Hospital Corporation
- Inventors: Clifford J. Woolf; Brian Wainger; Evangelos Kiskinis; Kevin Eggan
- Web page: https://patentgrep.com/patent/US9517223B2

## CPC

- A61K 31/325: Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145)
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/549: having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- G01N 33/4836: {using multielectrode arrays}
- G01N 33/502: {for testing non-proliferative effects}
- G01N 33/5058: {Neurological cells}
- G01N 2500/10: involving cells
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention is based on the discovery that motor neurons derived from patients with a neurodegenerative disease have decreased delayed rectifier potassium current and increased persistent sodium current compared to motor neurons derived from control healthy individuals. The present invention is also based on the discovery that the class of compounds known as “potassium channel openers” can be used to treat neurodegenerative diseases, including ALS, Parkinson's disease, Alzheimer's disease, epilepsy, and pain.

## Claims

### Claim 1

A method of diagnosing a subject with amyotrophic lateral sclerosis (ALS), the method comprising:
providing a motor neuron from the subject;
determining a level of activity of the motor neuron;
comparing the level of activity of the motor neuron with a reference level of activity of a motor neuron; and
diagnosing the subject as having ALS if the level of activity of the motor neuron is higher than the reference level of activity.

### Claim 2 (depends on 1)

The method of claim 1, wherein determining a level of activity of the motor neuron comprises measuring an action potential of the motor neuron.

### Claim 3 (depends on 1)

The method of claim 1, wherein determining a level of activity of the motor neuron comprises patch clamp recording or extracellular multi-electrode array recording.

### Claim 4

A method of treating, or reducing a risk of developing, ALS in a subject, the method comprising:
providing a motor neuron from a subject;
determining a level of activity of the motor neuron;
comparing the level of activity of the motor neuron with a reference level of activity of a motor neuron;
identifying the subject as having, or at increased risk of developing, ALS if the level of activity of the motor neuron is higher than the reference level of activity; and
administering to the subject identified as having or at increased risk of developing ALS a therapeutically effective amount of a potassium channel opener, thereby treating or reducing the risk of developing ALS in the subject.

### Claim 5 (depends on 4)

The method of claim 4, wherein the ALS is familial ALS or sporadic ALS.

### Claim 6 (depends on 4)

The method of claim 4, wherein the potassium channel opener is a KCNQ/Kv7 channel opener, a KATP channel opener, a G protein-coupled inwardly-rectifying potassium channel opener, a voltage-gated Ca2+-activated potassium channel opener, or an inward rectifier potassium channel opener.

### Claim 7 (depends on 4)

The method of claim 4, wherein the potassium channel opener is retigabine, a halogenated derivative of retigabine, a fluorinated derivative of retigabine, meclofenamic acid, diclofenac, BMS-204352, diazoxide, minoxidil, nicorandil, pinacidil, levcromakalim, or flupirtine.

### Claim 8 (depends on 4)

The method of claim 4, wherein the potassium channel opener is retigabine.

### Claim 9 (depends on 4)

The method of claim 4, the method further comprising administering to the subject an anti-neurodegenerative therapy.

### Claim 10 (depends on 9)

The method of claim 9, wherein the anti-neurodegenerative therapy is riluzole.

### Claim 11

A method of identifying a candidate compound to treat ALS, the method comprising:
providing a motor neuron from a subject with ALS or a motor neuron derived from a subject with ALS;
contacting the motor neuron with a test compound;
determining a level of activity of the motor neuron;
comparing the level of activity of the motor neuron in the presence of the test compound with a level of activity of the motor neuron in the absence of the test compound; and
selecting the test compound as a candidate compound if there is a lower level of activity of the motor neuron in the presence of the test compound than in its absence.

### Claim 12 (depends on 11)

The method of claim 11, wherein determining a level of activity of the motor neuron comprises measuring an action potential of the motor neuron.

### Claim 13 (depends on 11)

The method of claim 11, wherein determining a level of activity of the motor neuron comprises patch clamp recording or extracellular multi-electrode array recording.

### Claim 14 (depends on 11)

The method of claim 11, wherein the test compound is selected from the group consisting of polypeptides, small molecules, ribonucleic acids, and deoxyribonucleic acids.

### Claim 15 (depends on 11)

The method of claim 11, wherein the method further comprises determining whether the candidate compound increases survival of the motor neuron.

### Claim 16 (depends on 11)

The method of claim 11, the method further comprising:
determining whether the candidate compound reduces a symptom of ALS in an animal model, wherein a candidate compound that reduces a symptom of ALS is a candidate compound to treat the symptom of ALS.

### Claim 17 (depends on 1)

The method of claim 1, wherein the method further comprises administering to a subject diagnosed as having ALS a therapeutically effective amount of a potassium channel opener, thereby treating the ALS in the subject.