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Review
. 2023 May 4;30(5):512-529.
doi: 10.1016/j.stem.2023.03.017. Epub 2023 Apr 20.

Advancing cell therapy for neurodegenerative diseases

Sally Temple  1
Affiliations
Review

Advancing cell therapy for neurodegenerative diseases

Sally Temple. Cell Stem Cell. .

Abstract

Cell-based therapies are being developed for various neurodegenerative diseases that affect the central nervous system (CNS). Concomitantly, the roles of individual cell types in neurodegenerative pathology are being uncovered by genetic and single-cell studies. With a greater understanding of cellular contributions to health and disease and with the arrival of promising approaches to modulate them, effective therapeutic cell products are now emerging. This review examines how the ability to generate diverse CNS cell types from stem cells, along with a deeper understanding of cell-type-specific functions and pathology, is advancing preclinical development of cell products for the treatment of neurodegenerative diseases.

Keywords: Alzheimer disease; GABAergic neurons; Parkinson disease; age-related macular degeneration; astrocytes; central nervous system; dopaminergic neurons; frontotemporal dementia; microglia; neurodegenerative disease; neurons; oligodendrocytes; organoids; photoreceptors; preclinical studies; progressive supranuclear palsy; retina; retinal pigment epithelium; stem cell therapy; transplantation.

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Conflict of interest statement

Declaration of interests S.T. is co-founder of Luxa Biotech developing an RPE therapy for AMD and has patents related to RPE cell therapy: retinal pigment epithelial stem cells, patent number: 8481313; methods of treating a retinal disease by retinal pigment epithelial stem cells, patent number: 10034916. S.T. has advised BlueRock Therapeutics, Vita Therapeutics, and SANA Biotechnology.

Figures

Figure 1:
Figure 1:. Primary functional impact of neurodegenerative diseases and affected brain regions.
Patients experience symptoms that are primarily related to the particular neuronal and glial cell degeneration that occurs in different CNS areas in different diseases.
Figure 2:
Figure 2:. Examples of hPSC protocols to generate the major CNS cell types affected in neurodegenerative diseases.
An overview showing the key molecules applied and the approximate time taken to generate the cell products. AA=Ascorbic Acid; ACTA=Activin A; BDNF=brain derived neurotrophic factor; CHIR=CHIR99021, GSK3 Inhibitor, WNT activator; DAPT= gamma secretase inhibitor, Notch pathway inhibitor; dbcAMP=dibutyryl cyclic AMP; DKK1=dickkopf 1, WNT inhibitor; DM=Dorsomorphin, ALK2, ALK3, and ALK6 inhibitor; DMH-1= ALK1, ALK2, and ALK3 inhibitor; EB=Embryoid body; EGF=epidermal growth factor; FGF2=fibroblast growth factor 2; FGF8=fibroblast growth factor 8; FBS=fetal bovine serum; GDNF=glial cell derived growth factor; IGF1=insulin like growth factor 1; IL3=interleukin 3; IL6=interleukin 6; IL34=interleukin 34; IWP=WNT production inhibitor; IWR=WNT response inhibitor; LDN=LDN193189, ALK2 and ALK3 inhibitor; LiCl=Lithium chloride; LIF=Leukemia inhibitory Factor; M-CSF1= macrophage colony stimulating factor; NAM=Nicotinamide; NOG=Noggin; NT3=Neurotrophin 3; P=Passage; PD=PD0332991, CDK4/6 inhibitor; PDGFBB=platelet derived growth factor BB; PM=Purmorphamine; PVA=polyvinyl alcohol; RA=retinoic acid; SAG=sonic hedgehog signaling agonist; SB=SB431542, ALK4, 5 and 7 inhibitor; SCF= Stem Cell Factor; SSEA-1= stage-specific embryonic antigen 1; SHH=sonic hedgehog; T3=Triiodothyronine; TGFβ3=Transforming growth factor β-3; TPO=Thrombopoietin; VEGFA=vascular endothelial growth factor A; VPA=Valproic acid; XAV=XAV-939, Tankyrase blocker, inhibits WNT signaling.
Figure 3:
Figure 3:. Retinal cell replacement.
Examples of on-going studies and some of the challenges of using stem cell-derived retinal cell products, both single cell type and multi-cell grafts, to replace dysfunctional retinal cells. PR=photoreceptor.
Figure 4:
Figure 4:. Approaches to target microglia to combat neurodegenerative diseases.
Greater understanding of microglial contribution to neurodegenerative pathologies has led to biologics targeting microglial function and to cell replacement strategies using microglia or macrophages.
See this image and copyright information in PMC

References

    1. Stone WS et al. Neurodegenerative model of schizophrenia: Growing evidence to support a revisit. Schizophr Res 243, 154–162, doi: 10.1016/j.schres.2022.03.004 (2022). - DOI - PMC - PubMed
    1. Collaborators, G. B. D. D. F. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 7, e105–e125, doi: 10.1016/S2468-2667(21)00249-8 (2022). - DOI - PMC - PubMed
    1. Nandi A et al. Global and regional projections of the economic burden of Alzheimer’s disease and related dementias from 2019 to 2050: A value of statistical life approach. EClinicalMedicine 51, 101580, doi: 10.1016/j.eclinm.2022.101580 (2022). - DOI - PMC - PubMed
    1. Nagai M et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10, 615–622, doi: 10.1038/nn1876 (2007). - DOI - PMC - PubMed
    1. Vahsen BF et al. Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers. Nat Rev Neurol 17, 333–348, doi: 10.1038/s41582-021-00487-8 (2021). - DOI - PubMed

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