Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects

Workman, Michael J.; Lim, Ryan G.; Wu, Jie; Frank, Aaron; Ornelas, Loren; Panther, Lindsay; Galvez, Erick; Pérez, Daniel; Meepe, Imara; Lei, Susan; Valencia, Viviana; Gomez, Emilda; Liu, Chunyan; Moran, Ruby; Pinedo, Louis; Tsitkov, Stanislav; Ho, Ritchie; Kaye, Julia; Thompson, Terri G.; Rothstein, Jeffrey D.; Finkbeiner, Steven; Fraenkel, Ernest; Sareen, Dhruv; Thompson, Leslie M.; Svendsen, Clive N.

doi:10.1016/j.neuron.2023.01.010

Cited by 34 publications

(41 citation statements)

References 47 publications

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“…It was interesting that unsupervised clustering separated samples along PBMC type (T-cell or non-T-cell; Figure 2b); in the RNA-seq data, this was only observed when the gene set was constrained to four T-cell receptor associated genes. 26 Examining DARs associated with PBMC type, we found that regions located next to the T-cell receptor delta anti-sense 1 ( TRD-AS1 ) gene were dramatically less accessible in T-cell derived cell lines as would be expected (Figures 3a-b) due to T-cell receptor rearrangements. Beyond the TRD-AS1 regions, there are 180 DARs associated with PBMC type (FDR < 0.01, abs(log2FC) > 0.5); 25 of these regions are annotated as promoters.…”

Section: Resultsmentioning

confidence: 71%

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Disease related changes in ATAC-Seq of more than 450 iPSC-derived motor neuron lines from ALS patients and controls

Tsitkov,

Valentine,

Kozareva

et al. 2023

Preprint

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Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify robust ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

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Section: Resultsmentioning

confidence: 71%

“…Methods for generating iPSCs, quality control, and iPSC generation were described previously in Baxi et al 11 and Workman et al 26…”

Section: Generation Of Ipsc Motor Neuron Culturesmentioning

confidence: 99%

Disease related changes in ATAC-Seq of more than 450 iPSC-derived motor neuron lines from ALS patients and controls

Tsitkov,

Valentine,

Kozareva

et al. 2023

Preprint

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“…However, it remains technically challenging to enrich human motor neurons via single-cell profiling due to their sparsity in related tissues 58,59 . This makes stem cell differentiation as the standard method for exploring motor neuron biology and related conditions thus far 19,60 .…”

Section: Discussionmentioning

confidence: 99%

Deep learning modeling of rare noncoding genetic variants in human motor neurons definesCCDC146as a therapeutic target for ALS

Zhang,

Moll,

Rubin-Sigler

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by the selective and progressive death of motor neurons (MNs). Understanding the genetic and molecular factors influencing ALS survival is crucial for disease management and therapeutics. In this study, we introduce a deep learning-powered genetic analysis framework to link rare noncoding genetic variants to ALS survival. Using data from human induced pluripotent stem cell (iPSC)-derived MNs, this method prioritizes functional noncoding variants using deep learning, links cis-regulatory elements (CREs) to target genes using epigenomics data, and integrates these data through gene-level burden tests to identify survival-modifying variants, CREs, and genes. We apply this approach to analyze 6,715 ALS genomes, and pinpoint four novel rare noncoding variants associated with survival, including chr7:76,009,472:C>T linked toCCDC146. CRISPR-Cas9 editing of this variant increasesCCDC146expression in iPSC-derived MNs and exacerbates ALS-specific phenotypes, including TDP-43 mislocalization. SuppressingCCDC146with an antisense oligonucleotide (ASO), showing no toxicity, completely rescues ALS-associated survival defects in neurons derived from sporadic ALS patients and from carriers of the ALS-associated G4C2-repeat expansion withinC9ORF72. ASO targeting ofCCDC146may be a broadly effective therapeutic approach for ALS. Our framework provides a generic and powerful approach for studying noncoding genetics of complex human diseases.

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“…It is imperative to carefully control for these factors in future investigations to ensure reliable and meaningful results. This study serves as an important foundation for further exploration and emphasizes the significance of meticulously addressing sources of variability in subsequent iPSC‐based studies of neurological diseases (Workman et al., 2023).…”

Section: New Topics In Als Researchmentioning

confidence: 96%

“…To address this issue, Answer ALS has successfully generated an extensive collection of over 1000 iPSC lines derived from both healthy individuals and those diagnosed with ALS, accompanied by valuable clinical and whole-genome sequencing data. (Workman et al, 2023).…”

Section: Large Scale Library Of Ipscs-mns From Als Patientsmentioning

confidence: 99%

Induced pluripotent stem cells‐based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

Okano,

Morimoto,

Kato

et al. 2023

Journal of Neurochemistry

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It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs‐based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs‐based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS‐specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double‐blind, randomized, placebo‐controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient‐derived iPSCs‐motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA‐seq data showed that ROPI treatment suppressed the sterol regulatory element‐binding protein 2‐dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.

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Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects

Cited by 34 publications

References 47 publications

Disease related changes in ATAC-Seq of more than 450 iPSC-derived motor neuron lines from ALS patients and controls

Disease related changes in ATAC-Seq of more than 450 iPSC-derived motor neuron lines from ALS patients and controls

Deep learning modeling of rare noncoding genetic variants in human motor neurons definesCCDC146as a therapeutic target for ALS

Induced pluripotent stem cells‐based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

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