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

a neurodegenerative disease and composition technology, applied in the field of lserine compositions, methods and uses for treating neurodegenerative diseases and disorders, to achieve the effect of preventing, reducing or inhibiting the onset, severity, frequency or duration of one or more symptoms

Inactive Publication Date: 2013-06-20
THE INST FOR ETHNOMEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]As disclosed herein, L-Serine can block the insertion of BMAA in human cell cultures, preventing protein misfolding. Significantly, human cells that are at risk of undergoing programmed cell death via apoptosis can be rescued with the addition of L-Serine.
[0009]Accordingly, L-serine, as well as L-serine precursors, L-serine derivatives and L-serine conjugates, is a drug candidate for the treatment, amelioration and / or prevention of protein aggregation / tangles / plaques and diseases associated with protein aggregation / tangles / plaques such as Alzheimer's disease (AD), Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and as well as a treatment that can slow or stop disease progression or continuing neurodegeneration.
[0011]In accordance with the invention, there are also provided methods and uses for L-serine, or a precursor, derivative or conjugate of L-serine in: 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; 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; and treating a neurological disease or disorder caused or characterized by misfolding or aggregation of one or more proteins in a subject. In one embodiment, a method or use includes 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. In another embodiment, a method or use includes 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. In a further embodiment, a method or use includes 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.

Problems solved by technology

However such rare errors which result in the mischarging of tRNA synthetase by the wrong amino acid can result in misfolded or truncated proteins, and subsequent cell damage, such as in the sti (sticky) mutation in mice where alanine is substituted for glutamic acid, resulting in neurodegeneration (Lee, et al., Nature 443, 50-55 (2006)).

Method used

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

Examples

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example 1

[0103]This example describes various materials and methods.

Materials & Methods

[0104]MRC-5 cells were from American Tissue and Cell Culture (Virginia, USA). SH-SY5Y cells were from the European Collection of Cell Culture (ECACC). 3H-BMAA (80 Ci / mmol, 0.5 mCi / mL) was obtained from American Radiolabeled Chemicals. Dulbecco's modification of Eagle's minimum essential medium (DMEM) and HAMS F12 were from JRH biosciences, (Lenexa, Kansans, USA). BMAA, dithiothreitol, L-serine, D-serine, acridine orange, ethidium bromide, cycloheximide and SDS were from Sigma Chemical Co. (Sigma-Aldrich, Castle Hill, NSW, Australia). BCA protein reagent was from Pierce Biotechnology (Rockford, Ill., USA). BD Pharminigen™ Annexin V-FITC apoptosis detection kit was from BD Biosciences (Sydney Australia). Water was from a Milli Q 4 stage system (Millipore-Waters, Lane Cove, NSW, Australia). All HPLC equipment was supplied by the Shimadzu Corporation (Kyoto, Japan) except the column (Nova-Pak® C18 4 μM 3.9×300...

example 2

[0120]This example describes data indicating that BMAA is incorporated into proteins, which can lead to protein misfolding / aggregation, and which incorporation and misfolding / aggregation is inhibited by L-serine.

[0121]Incubation of human MRC-5 fibroblasts with 3H-BMAA in culture medium depleted in amino acids resulted in a time-dependent increase in radiolabel in cell lysates (FIG. 1A), a proportion of which was associated with cell proteins (FIG. 1B). Co-incubation of MRC-5 cells with 3H-BMAA along with the protein synthesis inhibitor CHX significantly reduced the amount of radiolabel in the protein fraction (FIG. 2). CHX inhibited incorporation of the protein amino acid 3H-leucine into proteins to the same extent as 3H-BMAA (FIG. 2) suggesting that 3H-BMAA was incorporated into proteins by a protein synthesis-dependent mechanism. 3H-BMAA was also found to be protein associated after incubation with human primary endothelial cells (HUVEC) and human neuroblastoma cells (SH-SY5Y), th...

example 3

[0128]This example describes data indicating that L-Serine rescues Drosophila melanogaster (fruit flies) from BMAA induced mortality, and additional useful models.

[0129]APP is evolutionarily conserved from invertebrates to vertebrates. This allows research to be performed on APP in Drosophila fruit flies, to study human diseases such as Alzheimer's disease. The Drosophila model was used to characterize how BMAA influences the production of the APP-derived fragments, especially the amyloidogenic fragments.

The Drosophila melanogaster (fruit fly) insect model is a convenient invertebrate system to measure important features of a human disease, including plaque formation, memory loss, social interactions, and the overall neuronal structure of a model organism. Fruit flies also engineered to produce extra human Aβ will be fed BMAA and the resulting increase or decrease in plaque inducing Aβ will be measured. Flies are an excellent model because their genetic characteristics have been wel...

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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).

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. Application No. 61 / 562,194, filed Nov. 21, 2011, which application is expressly incorporated by reference herein in its entirety.INTRODUCTION[0002]Protein translation is a highly efficient and accurate process for assembling the 20 standard amino acids into proteins. Error rates in translation are relatively rare (1 in 103 to 104) and rely on the ability of the system to discriminate between the 20 protein (or canonical) amino acids (Zaher, et al., Cell 136, 746-762 (2009)). However such rare errors which result in the mischarging of tRNA synthetase by the wrong amino acid can result in misfolded or truncated proteins, and subsequent cell damage, such as in the sti (sticky) mutation in mice where alanine is substituted for glutamic acid, resulting in neurodegeneration (Lee, et al., Nature 443, 50-55 (2006)). We here report that a nonprotein amino acid produced by cyanobacteria, β-methylamino-L-alanine (BMAA), can be ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/198
CPCA01K67/027A61K31/198A61P1/00A61P1/14A61P11/00A61P13/00A61P21/00A61P25/00A61P25/08A61P25/14A61P25/16A61P25/20A61P25/22A61P25/28A61P3/02A61P39/00A61K38/00A61P43/00
Inventor RODGERS, KENNETHDUNLOP, RACHAELCOX, PAUL A.
Owner THE INST FOR ETHNOMEDICINE
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