A Chemical Recipe for Generation of Clinical-Grade Striatal Neurons from hESCs

Wu, Menghua; Zhang, Da; Bi, Chunying; Zhu, Wenliang; Xia, Longkuo; Teng, Zhao‐Qian; Hu, Baoyang; Wu, Yihui

doi:10.1016/j.stemcr.2018.08.005

Cited by 31 publications

(38 citation statements)

References 42 publications

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“…However, human embryonic stem cell-derived neural stem cells (hNSCs) transplanted into the striatum of HD mice (both R6/2 and Q140 knockin) resulted in symptomatic improvement (Reidling et al, 2018). Protocols for the development of clinical-grade striatal neurons have now been published (Wu et al, 2018). There is the potential to carry out ex vivo genetic modification of autologous iPSC-derived cells to produce neurotrophic factors and subsequently transplant them back into the CNS of patients (Gowing et al, 2017), an approach that is being taken forward for the treatment of ALS.…”

Section: Biomarkers Of Target Engagementmentioning

confidence: 99%

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Tabrizi

Ghosh

Leavitt

2019

Neuron

262

190

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Section: Biomarkers Of Target Engagementmentioning

confidence: 99%

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Tabrizi

Ghosh

Leavitt

2019

Neuron

262

190

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“…Medium was replaced daily. hESCs were differentiated into striatal neurons using a previously described protocol ( 106 ) ( SI Appendix ).…”

Section: Methodsmentioning

confidence: 99%

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Sharma

Sumitha

Shahani

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

106

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Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain’s striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that thecGASmRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5andCxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed thatLC3AandLC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.

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“…Many of the symptoms observed in HD patients are highly related to the loss of MSNs in the striatum 6 and can be mimicked in rodent 7 , pig 8 , and non-human primate 9 models. Previous studies have achieved some success in HD animal models through cell transplantation [10][11][12] or using antisense oligonucleotides 13,14 and CRISPR/Cas9 gene editing technology 15 to reduce the mHtt level. Tetrabenazine has been used to treat chorea in HD and other movement disorders but with significant side effects 16 .…”

mentioning

confidence: 99%

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease

et al. 2020

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Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32 + medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.

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A Chemical Recipe for Generation of Clinical-Grade Striatal Neurons from hESCs

Cited by 31 publications

References 42 publications

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease

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