# US 2013/0156846 A1 · L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders

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- Number: US 2013/0156846 A1
- Document ID: US20130156846A1
- Status: Published application
- Kind: A1
- Application number: 13/683,821
- Filed: 2012-11-21
- Published: 2013-06-20
- Earliest claimed: 2011-11-21
- Assignees: The Institute for Ethnomedicine
- Inventors: Kenneth Rodgers; Rachael Dunlop; Paul A. Cox
- Web page: https://patentgrep.com/patent/US20130156846A1

## CPC

- A01K 67/027: New or modified breeds of vertebrates
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- 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
- A61P 39/00: General protective or antinoxious agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- 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

## Abstract

L-serine, L-serine precursors, L-serine derivatives and L-serine conjugates for treatment, amelioration and/or prevention of protein aggregation/tangles/plaques and diseases associated with protein aggregation/tangles/plaques. In particular, treatments and uses for L-serine, L-serine precursors, L-serine derivatives and L-serine conjugates include Alzheimer's disease (AD), Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington disease (HD).

## Claims

### Claim 1

A method of preventing, inhibiting or reducing incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into one or more proteins of a mammalian cell, comprising contacting the cell with L-serine, or a precursor, derivative or conjugate of L-serine, in an amount sufficient to prevent, inhibit or reduce incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into the protein.

### Claim 2

A method of preventing, inhibiting or reducing misfolding or aggregation of one or more proteins in a mammalian cell, comprising contacting the cell with L-serine, or a precursor, derivative or conjugate of L-serine, in an amount sufficient to prevent, inhibit or reduce misfolding or aggregation of the protein.

### Claim 3

A method of reducing or decreasing risk of a neurological disease or disorder caused or characterized by misfolding or aggregation of one or more proteins in a subject, comprising administering to the subject L-serine, or a precursor, derivative or conjugate of L-serine, in an amount sufficient to reduce or decrease risk of the neurological disease or disorder caused or characterized by misfolding or aggregation of one or more proteins.

### Claim 4

A method of stabilizing, or reducing or inhibiting progression of, a neurological disease or disorder caused or characterized by misfolding or aggregation of one or more proteins in a subject, comprising administering to the subject L-serine, or a precursor, derivative or conjugate of L-serine, in an amount sufficient to stabilize, or reduce or inhibit progression of, a neurological disease or disorder a caused or characterized by misfolding or aggregation of one or more proteins.

### Claim 5

A method of treating a neurological disease or disorder caused or characterized by misfolding or aggregation of one or more proteins in a subject, comprising administering to the subject L-serine, or a precursor, derivative or conjugate of L-serine, in an amount sufficient to treat the neurological disease or disorder caused or characterized by misfolding or aggregation of one or more proteins.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the cell or subject is human.

### Claim 7 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the cell is a neuron or a glial cell.

### Claim 8 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the protein is TAR DNA-binding protein 43 (TDP-43) or alpha-synuclein.

### Claim 9 (depends on 1)

The method of claim 1, wherein the derivative or isomer of BMAA comprises 2,4-diaminobutyric acid (2,4-DAB), 2,3-diaminobutyric acid (2,3-DAB), N-(2-aminoethyl)glycine (AEG), or β-amino-N-methyl-alanine (BAMA).

### Claim 10 (depends on 3, 4, 5)

The method of any of claims 3 to 5, wherein the neurological disease or disorder is histologically characterized by protein misfolding or protein aggregates.

### Claim 11 (depends on 3, 4, 5)

The method of any of claims 3 to 5, wherein the neurological disease or disorder is a motor or cognitive deficiency.

### Claim 12 (depends on 3, 4, 5)

The method of any of claims 3 to 5, wherein the neurological disease or disorder is Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP), Lewy Body Dementia (LBD), Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC), Huntington's disease (HD), Pick's disease or Frontotemporal Dementia (FTD).

### Claim 13 (depends on 3, 4, 5)

The method of any of claims 3 to 5, wherein a symptom of the neurological disease or disorder is motor or cognitive deficiency; fatigue; tremors; ataxia; slurred, thick or irregular speech; muscle cramps, twitching, atrophy or weakness; shortness of breath; eating, breathing or swallowing difficulty; short term or long term memory loss; difficulty concentrating or completing familiar or routine tasks; space and time confusion; vision, color or sign recognition loss; depth perception loss, speaking or writing difficulty; loss of judgment; vocabulary loss; moodiness; irritability; aggression; paranoia; delusions; withdrawal from social engagement; stiffness or rigidity; loss of fine or gross motor control; slowing of movement; impaired balance; body instability; posture or gait abnormality; shuffling walk; reduced coordination; physical instability; unsteady gait; motor dysfunction; jerky body movement; slowed saccadic eye movement; body rigidity; seizure; difficulty chewing, eating, swallowing or speaking; deterioration in cognition/mental capabilities; dementia; sleep, behavioral or psychiatric abnormalities; difficulty in speech or thinking; behavioral changes; impaired regulation of social conduct; passivity; lethargy; social withdrawal; inertia; over-activity; pacing; wandering; loss of balance; lunging forward when mobilizing; fast walking; imbalance, e.g., bumping into objects or people; falls; changes in personality; slowing of movement; loss of inhibition or ability to organize information; slurred speech; difficult swallowing; opthalmoparesis or impaired eye movement; impaired eyelid function; facial muscle contracture; Neck dystonia or backward tilt of the head with stiffening of neck muscles; sleep disruption; urinary/bowel incontinence; or parkinsonism.
The method of any of claims 3 to 5, wherein onset, severity, frequency, or duration of one or more symptoms of the neurological disease or disorder is prevented, reduced or inhibited.

### Claim 14 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine comprises an L-serine polymer (polyserine), a salt of L-serine, an alkylated L-serine or an L-serine lipid.

### Claim 15 (depends on 14)

The method of claim 14, wherein the L-serine salt comprises a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, or an ammonium salt of L-serine.

### Claim 16 (depends on 14)

The method of claim 14, wherein the alkylated L-serine has an alkyl group with 1-20 carbon atoms.

### Claim 17 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the derivative is an L-serine ester, an L-serine di-ester, a phosphate ester of L-serine, a sulfate or sulfonate ester of L-serine, a pegylated L-serine, a lipidated L-serine or an L-serine with one or more polyethylene glycol (PEG) moieties.

### Claim 18 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine precursor is L-phosphoserine.

### Claim 19 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine comprises liposomes or micelles.

### Claim 20 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, comprises a pharmaceutical composition or formulation.

### Claim 21 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered orally, by injection, by infusion, by intubation, via catheter or intracranially to the subject.

### Claim 22 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered at least once daily for at least one week to the subject.

### Claim 23 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered for at least two, three, four, five, six, seven, 8, 9, 10, 11 or 12 weeks to the subject.

### Claim 24 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered for at least one, two, three, four, five, six, seven, 8, 9, 10, 11 or 12 months to the subject.

### Claim 25 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered at a dose of about 1-10 mg/day, 10-25 mg/day, 25-50 mg/day, 50-100 mg/day, 100-250 mg/day, 250-500 mg/day, 500-750 mg/day, 750-1,000 mg/day, 1,000-2,000 mg/day, 2,000-3,000 mg/day, 3,000-4,000 mg/day, 4,000-5,000 mg/day, 5,000-7,500 mg/day, 7,500-10,000 mg/day, 10-15 g/day, 15-20 g/day, 20-25 g/day, 25-30 g/day, 30-40 g/day, 40-50 g/day 50-75 g/day or 75-100 g/day to the subject.

### Claim 26 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered at a dose of about 1-10 mg/kg body weight, 10-25 mg/kg body weight, 25-50 mg/kg body weight, 50-100 mg/kg body weight, 100-250 mg/kg body weight, 250-500 mg/kg body weight, 500-750 mg/kg body weight, or 750-1,000 mg/kg body weight to the subject.

### Claim 27 (depends on 1, 2, 3, 4, 5)

The method of any of claims 1 to 5, wherein the L-serine, precursor, derivative or conjugate of L-serine, is administered at a dose of about 1-10 mg/kg body weight per day, 10-25 mg/kg body weight per day, 25-50 mg/kg body weight per day, 50-100 mg/kg body weight per day, 100-250 mg/kg body weight per day, 250-500 mg/kg body weight per day, 500-750 mg/kg body weight per day, or 750-1,000 mg/kg body weight per day to the subject

### Claim 28

A pharmaceutical composition or formulation, comprising L-serine, or a precursor, derivative or conjugate of L-serine, wherein the composition or formulation is suitable for administration or delivery orally, by injection, by infusion, by intubation, via catheter, intraspinally, or intracranially to a subject.

### Claim 29

A method for identifying an agent that reduces or inhibits or prevents incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into a protein, comprising:
a) contacting a serine racemase with a test compound in the presence of a L-serine under conditions where the L-serine would be converted to D-serine by the serine racemase; and
b) determining if the test compound inhibits or reduces conversion of the L-serine to D-serine by the serine racemase, and if the test compound inhibits or reduces conversion of the L-serine to D-serine by the serine racemase the test compound is identified as an agent that reduces or inhibits or prevents incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into a protein.

### Claim 30

A method of identifying a candidate agent for reducing or inhibiting or preventing incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into a protein, comprising:
a) contacting a serine racemase with L-serine under conditions where the L-serine would be converted to D-serine by the serine racemase in the presence of a test agent; and
b) determining if the test agent inhibits or reduces conversion of the L-serine to D-serine by the serine racemase, wherein an inhibition or reduction identifies the test agent as a candidate agent for reducing or inhibiting or preventing incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into a protein.

### Claim 31

A method of screening for an agent that reduces or inhibits or prevents incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into a protein, comprising:
a) contacting a serine racemase with L-serine under conditions where the L-serine would be converted to D-serine by the serine racemase in the presence a test agent; and
b) determining if the test agent inhibits or reduces conversion of the L-serine to D-serine by the serine racemase, thereby screening for an agent that reduces or inhibits or prevents incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA, into a protein.

### Claim 32 (depends on 29, 30, 31)

The method of any of claims 29 to 31, comprising measuring the activity of the agent to reduce or inhibit or prevent incorporation of β-N-methylamino-L-alanine (BMAA), or a derivative or isomer of BMAA into a protein in a cell.