L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders

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).

What is claimed: 
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         6 . The method of any of  claims 1  to  5 , wherein the cell or subject is human. 
     
     
         7 . The method of any of  claims 1  to  5 , wherein the cell is a neuron or a glial cell. 
     
     
         8 . The method of any of  claims 1  to  5 , wherein the protein is TAR DNA-binding protein 43 (TDP-43) or alpha-synuclein. 
     
     
         9 . 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). 
     
     
         10 . The method of any of  claims 3  to  5 , wherein the neurological disease or disorder is histologically characterized by protein misfolding or protein aggregates. 
     
     
         11 . The method of any of  claims 3  to  5 , wherein the neurological disease or disorder is a motor or cognitive deficiency. 
     
     
         12 . 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). 
     
     
         13 . 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. 
 
     
     
         14 . 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. 
     
     
         15 . 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. 
     
     
         16 . The method of  claim 14 , wherein the alkylated L-serine has an alkyl group with 1-20 carbon atoms. 
     
     
         17 . 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. 
     
     
         18 . The method of any of  claims 1  to  5 , wherein the L-serine precursor is L-phosphoserine. 
     
     
         19 . The method of any of  claims 1  to  5 , wherein the L-serine, precursor, derivative or conjugate of L-serine comprises liposomes or micelles. 
     
     
         20 . 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. 
     
     
         21 . 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. 
     
     
         22 . 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. 
     
     
         23 . 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. 
     
     
         24 . 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. 
     
     
         25 . 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. 
     
     
         26 . 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. 
     
     
         27 . 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 
     
     
         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. 
     
     
         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. 
 
     
     
         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. 
 
     
     
         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. 
 
     
     
         32 . 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.