Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities

Kim, Tae Wan; Koo, So Yeon; Studer, Lorenz

doi:10.3389/fcell.2020.00729

Cited by 74 publications

(63 citation statements)

References 108 publications

(171 reference statements)

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“…In many brain regions, Single-cell RNA sequencing (scRNA-seq) has allowed researchers to identify various cell subpopulations, pinpoint gene signatures and novel cell markers (Cuevas-Diaz Duran et al, 2017 ; Ofengeim et al, 2017 ). Cell replacement has been a long-standing and realistic objective for the treatment of PD (Kim et al, 2020 ; Parmar et al, 2020 ). To uncover the previously unknown cellular diversity in a clinically relevant cell replacement PD model, scRNA-seq was used in the experiment by Tiklová et al ( 2020b ).…”

Section: Nurr 1 At a Glancementioning

confidence: 99%

Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

Kambey

Kanwore

Ayanlaja

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder’s neuropathology is reasonably well known, its etiology remains a mystery, making it challenging to aim therapy. Glial cell-line derived neurotrophic factor (GDNF) remains an auspicious therapeutic molecule for treating PD. Neurotrophic factor derived from glial cell lines is effective in rodents and nonhuman primates, but clinical findings have been equivocal. Laborious exertions have been made over the past few decades to improve and assess GDNF in treating PD (clinical studies). Definitive clinical trials have, however, failed to demonstrate a survival advantage. Consequently, there seemed to be a doubt as to whether GDNF has merit in the potential treatment of PD. The purpose of this cutting edge review is to speculate as to why the clinical trials have failed to meet the primary endpoint. We introduce a hypothesis, “Failure of GDNF in clinical trials succumbed by nuclear receptor-related factor 1 (Nurr1) shortfall.” We demonstrate how Nurr1 binds to GDNF to induce dopaminergic neuron synthesis. Due to its undisputable neuro-protection aptitude, we display Nurr1 (also called Nr4a2) as a promising therapeutic target for PD.

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Section: Nurr 1 At a Glancementioning

confidence: 99%

Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

Kambey

Kanwore

Ayanlaja

et al. 2021

Front. Aging Neurosci.

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“…The use of human iPSCs for cell therapy avoids need for long immunosuppressive treatments, risk of graft rejection and ethical concerns related to the use of human embryos. In this regard, it has been recently shown that dopaminergic progenitors derived from clinical-grade human ESC or iPSC lines are safe and effective for cell-based therapy in PD ( Doi et al, 2020 ; Kim et al, 2020 ). Most importantly, human iPSC transplantation into the putamen of a PD patient suggested graft survival as well as improvement of PD symptoms at 18–24 months after surgery ( Schweitzer et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Replacement in Stem Cell Therapy for Stroke: Filling the Gap

Palma-Tortosa

Martin

Kokaia

et al. 2021

Front. Cell Dev. Biol.

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Stem cell therapy using human skin-derived neural precursors holds much promise for the treatment of stroke patients. Two main mechanisms have been proposed to give rise to the improved recovery in animal models of stroke after transplantation of these cells. First, the so called by-stander effect, which could modulate the environment during early phases after brain tissue damage, resulting in moderate improvements in the outcome of the insult. Second, the neuronal replacement and functional integration of grafted cells into the impaired brain circuitry, which will result in optimum long-term structural and functional repair. Recently developed sophisticated research tools like optogenetic control of neuronal activity and rabies virus monosynaptic tracing, among others, have made it possible to provide solid evidence about the functional integration of grafted cells and its contribution to improved recovery in animal models of brain damage. Moreover, previous clinical trials in patients with Parkinson’s Disease represent a proof of principle that stem cell-based neuronal replacement could work in humans. Our studies with in vivo and ex vivo transplantation of human skin-derived cells neurons in animal model of stroke and organotypic cultures of adult human cortex, respectively, also support the hypothesis that human somatic cells reprogrammed into neurons can get integrated in the human lesioned neuronal circuitry. In the present short review, we summarized our data and recent studies from other groups supporting the above hypothesis and opening new avenues for development of the future clinical applications.

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“…A major challenge in regenerative medicine approaches to treat neurodegenerative diseases, including HD, is enabling long-term assessment of cell fate, functional properties and potential rescue of disease-associated phenotypes (Jia et al, 2020; Kim et al, 2020). Here we evaluated whether hNSCs implanted in the striata of zQ175 mice are viable and integrate into the host tissue at a time point of 8 months after grafting (equating to roughly a third of the captive’s mouse 2-year lifespan).…”

Section: Discussionmentioning

confidence: 99%

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

Thompson

Holley

Reidling

et al. 2021

Preprint

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Huntington’s disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

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Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities

Cited by 74 publications

References 108 publications

Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review

Neuronal Replacement in Stem Cell Therapy for Stroke: Filling the Gap

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

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