Generation of neural stem cells from human trophoblast stem cells
Inventors
Lee, Jau-Nan • Lee, Tony Tung-Ying • Lee, Yuta • Tsai, Eing-Mei
Assignees
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Publication Number
US-11891623-B2
Publication Date
2024-02-06
Expiration Date
Abstract
Provided herein are isolated neural stem cells and methods of making neural stem cells from human trophoblast stem cells. The isolated neural stem cells can be immune privileged and express one or more protein(s). Also provided are methods for treatment of neurodegenerative diseases using suitable preparations comprising the isolated neural stem cells.
Core Innovation
The work derives and characterizes human trophoblastic stem cells and uses these cells to inform properties of human neural stem cells. The neural stem cell characteristics include expression of Cdx2, Nanog, Sox2, Ngn-3, RARβ, RXRα, RXRβ, RALDH-2, and RALDH-3, together with RXRα/RARβ signaling and RALDH-2 and RALDH-3 activities.
The description includes pathway components including Wnt2B, Fzd6, β-catenin, Akt3/mTOR, and translation pathways, linked to downstream transcriptional regulators affecting dopaminergic genes. Retinoic acid signaling is linked to downstream pathways involving RXRα/RARβ/c-Src/Stat3/Nanog and Wnt2B/β-catenin/HDAC6.
The work reports functional evaluation of transplantation into a rat Parkinson’s disease model, with assessment of dopaminergic neuron regeneration and function, including TH, CREB1, and teratoma absence in SCID mice. The disclosed neural stem cells are described as having low levels of expression or an absence of expression of CD33 or CD133 cell surface proteins as compared to a human trophoblastic stem cell, together with absence of HLA-DR.
Claims Coverage
The independent claim covers a treatment method for neurological disorders by administering a human neural stem cell with a defined protein expression profile and a defined comparison to human trophoblastic stem cells, using injection or implantation. Across the dependent claims, additional inventive features specify immune-response constraints, refine antigen and protein expression comparisons, narrow the anatomical administration site and differentiation outcome, specify neuron subtype differentiation, and require production of specific neurotransmitter/synapse proteins and ion-channel markers.
Treatment of neurological disorders by neural stem cell administration
A method of treating a neurological disorder in a subject in need thereof by administering at least one neural stem cell, wherein the neural stem cell is a human neural stem cell that expresses Cdx2, Nanog, Ngn3, RARβ, RXRα, RXRβ, RALDH-2, and RALDH-3 proteins and has low levels of expression or an absence of expression of CD33 or CD133 cell surface proteins as compared to a human trophoblastic stem cell.
Administration by injection or implantation
Wherein administering comprises injecting or implanting.
Immune-response constraint via immune activation or suppression
The at least one neural stem cell does not trigger or instead suppresses immune responses mediated by specified immune cell types in the subject.
Low or absent CD33 and CD133 cell surface protein expression relative to trophoblastic stem cells
The at least one neural stem cell has low or absent expression of the CD33 and CD133 cell surface proteins compared to a human trophoblastic stem cell.
Brain administration with neuron differentiation
Administering at least one neural stem cell into a subject’s brain, where the neural stem cell differentiates into a neuron following administration.
Neuron subtype differentiation
The neuron is specifically a dopaminergic neuron, glutaminergic neuron, serotonergic neuron, or gamma aminobutyric acid (GABAergic) neuron.
Production of neurotransmitter, synapse, and ion-channel markers
At least one neural stem cell produces specified neurotransmitter- and synapse-related proteins and ion-channel markers.
Overall claim coverage centers on administering human neural stem cells expressing a specified combination of Cdx2/Nanog/Ngn3 and retinoic-acid pathway proteins (RARβ, RXRα, RXRβ, RALDH-2, RALDH-3) while having low or absent CD33 or CD133 relative to human trophoblastic stem cells, with administration by injection or implantation. Dependent claims add immune-response constraints, refine CD33/CD133 expression comparisons, specify brain delivery and neuron differentiation, further restrict neuron subtype options, and require production of neurotransmitter, synapse, and ion-channel markers.
Stated Advantages
Improves behavioral impairments in Parkinson’s rat models.
Regenerates TH+ dopaminergic neurons.
Shows survival without tumor formation.
Shows survival without immunosuppression.
Teratoma absence in SCID mice.
Documented Applications
Treating Parkinson's disease.
Treating Alzheimer's disease.
Treating Huntington's disease.
Treating amyotrophic lateral sclerosis (ALS).
Treating Friedreich's ataxia.
Treating Lewy body disease.
Treating spinal muscular atrophy.
Treating multiple system atrophy.
Treating dementia.
Treating schizophrenia.
Treating paralysis.
Treating multiple sclerosis.
Treating a spinal cord injury.
Treating a brain injury.
Treating a cranial nerve disorder.
Treating a peripheral sensory neuropathy.
Treating epilepsy.
Treating a prion disorder.
Treating Creutzfeldt-Jakob disease.
Treating Alper's disease.
Treating cerebellar/spinocerebellar degeneration.
Treating Batten disease.
Treating corticobasal degeneration.
Treating Bell's palsy.
Treating Guillain-Barre syndrome.
Treating Pick's disease.
Treating autism.
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