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1. EP2782587 - STEM CELL-DERIVED NEURAL CELLS FOR CELL THERAPY IN NEUROLOGICAL DISORDERS

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Claims

1. An in-vitro method for inducing differentiation of oral mucosa stem cells (OMSC), the method comprising:

(a) incubating oral mucosa stem cells (OMSC) obtained from oral mucosa in a pre-differentiating medium capable of inducing the differentiation of OMSC toward a specific neural lineage for 24-96 hours, wherein the pre-differentiating medium comprises N-2 supplement, basic fibroblast growth factor 2 (bFGF) and epidermal growth factor (EGF); and

(b) incubating the OMSC of (a) in

a differentiating medium comprising 0.1-5% B27, 85-750 ng/mL Sonic Hedgehog, 30-300ng/mL Wnt-1, 30-300ng/mL FGF-8, 15-150 ng/mL BDNF, 15-150ng/mL bFGF, and 65-600 ng/mL ascorbic acid, for at least 11 days, and thereby differentiated into dopaminergic neural cells.
  2. The in-vitro method according to claim 1, comprising the steps of:

(a) incubating hOMSC for 48 to 72 hours in the pre-differentiation medium and

(b) incubating the hOMSC of (a) in a differentiation medium comprising 0.5% B27, 250 ng/mL Sonic Hedgehog, 100 ng/mL Wnt-1, 100ng/mL FGF-8, 50 ng/mL BDNF, 50 ng/mL bFGF, and 200 ┬ÁM ascorbic acid, for 13-15 days.


  3. A population of neural stem cells differentiated from pluripotent or multipotent stem cells derived from the oral mucosa by a method according to any one of claims 1-2, wherein the neural stem cells express Pitx3, Nurrl, Lmx1a, DAT and TH to a higher level compared neural stem cells derived from OMSCs that were not subjected to the treatment regimen of the method of claims 1 or 2.
  4. A pharmaceutical composition comprising a cell population according to claim 3.
  5. The cell population of claim 3, wherein the dopaminergic cells acquired a dopaminergic phenotype and a neuron-like morphology, express inherent transcription factors and tyrosine hydroxylase and exhibit regulated dopamine secretion into the medium.
  6. The cell population according to claim 5 for use in alleviating motoric and behavioral symptoms of Parkinson Disease, wherein the cell is implanted in the striatum or substantia nigra of a patient in need thereof.
  7. The cell population according to claim 3 for use in preventing or treating degenerative and traumatic disorders.
  8. The pharmaceutical composition according to claim 4 for use in the treatment of a neurological or psychiatric disease or disorder.
  9. The pharmaceutical composition for use according to claim 8,
wherein the neurological disease or disorder is a peripheral nervous system disease or disorder; or
wherein the neurological disease or disorder is selected from the group consisting of a motion disorder, a dissociative disorder, a mood disorder, an affective disorder, an addictive disorder and a convulsive disorder; or
wherein the neurological disease or disorder involves loss of neural tissue due to trauma; or
wherein the psychiatric disease or disorder is schizophrenia, depression or autism; or wherein the neurological disease or disorder is a central nervous system (CNS) disease or disorder.
  10. The composition for use of claim 9, wherein the CNS disease or disorder is a neurodegenerative disease or disorder.
  11. The composition for use of claim 10,
wherein the neurodegenerative disorder is a chronic disease or disorder selected from the group consisting of Parkinson's, multiple sclerosis, epilepsy, amyotrophic lateral sclerosis, diabetic neuropathy, glaucomatous neuropathy, Alzheimer's disease and Huntington's disease; or
wherein the neurodegenerative disorder is an acute disease or disorder selected from stroke, autoimmune encephalomyelitis.
  12. A cell population according to claim 3 for use in treating a neurological or psychiatric disease or disorder.
  13. The cell population for use according to claim 12, wherein the neural cell is a cell capable of secreting at least one neurotrophic factor (NTF), preferably wherein the at least one NTF is selected from the group consisting of: glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrotrophin-4/5; Neurturin (NTN), Neurotrophin-4, Persephin, artemin (ART), ciliary neurotrophic factor (CNTF), insulin growth factor-I (IGF-I), and Neublastin.