An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Li, Jonathan; Lim, Ryan G.; Kaye, Julia; Dardov, Victoria; Coyne, Alyssa N.; Wu, Jie; Milani, Pamela; Cheng, Andrew Tai Ann; Thompson, Terri G.; Ornelas, Loren; Frank, Aaron; Adam, Miriam; Bañuelos, Maria G.; Casale, Malcolm; Cox, Veerle; Escalante-Chong, Renan; Daigle, J. Gavin; Gomez, Emilda; Hayes, Lindsey; Holewenski, Ronald; Lei, Susan; Lenail, Alex; Lima, Leandro; Mandefro, Berhan; Matlock, Andrea; Panther, Lindsay; Patel-Murray, Natasha L.; Pham, Jacqueline T.; Ramamoorthy, Divya; Sachs, Karen; Shelley, Brandon; Stocksdale, Jennifer; Trost, Hannah; Wilhelm, Mark; Venkatraman, Vidya; Wassie, Brook T.; Wyman, Stacia K.; Yang, Stephanie; Eyk, Jennifer E. Van; Lloyd, Thomas E.; Finkbeiner, Steven; Rothstein, Jeffrey D.; Svendsen, Clive N.; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R.; Simmons, Zachary; Arcila‐Londono, Ximena; Lee, Edward B.; Deerlin, Vivianna M. Van; Shneider, Neil A.; Fraenkel, Ernest; Ostrow, Lyle W.; Baas, Frank; Zaitlen, Noah; Berry, James; Malaspina, Andrea; Fratta, Pietro; Cox, Gregory A.; Thompson, Leslie M.; Finkbeiner, Steve; Dardiotis, Efthimios; Miller, Timothy M.; Chandran, Siddharthan; Pal, Suvankar; Hornstein, Eran; MacGowan, Daniel; Heiman‐Patterson, Terry; Hammell, Molly; Patsopoulos, Nikolaos A.; Butovsky, Oleg; Dubnau, Josh; Nath, Avindra; Bowser, Robert; Harms, Matt; Poss, Mary; Phillips-Cremins, Jennifer E.; Crary, John F.; Atassi, Nazem; Lange, Dale J.; Adams, Darius; Stefanis, Leonidas; Gotkine, Marc; Baloh, Robert H.; Babu, Suma; Raj, Towfique; Paganoni, Sabrina; Shalem, Ophir; Smith, Colin; Zhang, Bin; Harris, Brent T.; Broce, Iris; Drory, Vivian E.; Ravits, John; McMillan, Corey T.; Menon, Vilas; Wu, Lani F.; Altschuler, Steven J.

doi:10.1016/j.isci.2021.103221

Cited by 34 publications

(13 citation statements)

References 126 publications

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“…In recent years, omics technologies have significantly contributed to uncover the biological heterogeneity of Amyotrophic lateral sclerosis (ALS) [ 114 ]. Recent work has combined iPSCs-derived motor neurons generated from different patients with a common ALS mutation with omics datasets to identify known and novel pathways, which were consistently dysregulated across all lines with the aim to include an additional 1,000 ALS-derived iPSC lines to define the molecular pathogenic signature for ALS [ 93 ]. Similar approach could be applied to characterise iPSCs-based models derived from patients with different stroke types to learn about early pathogenic events and develop new personalised treatments.…”

Section: Current and Potential Applications Of Human Ipscs In Functio...mentioning

confidence: 99%

Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants

Granata

2023

BMC Cardiovasc Disord

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Stroke is an important disease with unmet clinical need. To uncover novel paths for treatment, it is of critical importance to develop relevant laboratory models that may help to shed light on the pathophysiological mechanisms of stroke. Induced pluripotent stem cells (iPSCs) technology has enormous potential to advance our knowledge into stroke by creating novel human models for research and therapeutic testing. iPSCs models generated from patients with specific stroke types and specific genetic predisposition in combination with other state of art technologies including genome editing, multi-omics, 3D system, libraries screening, offer the opportunity to investigate disease-related pathways and identify potential novel therapeutic targets that can then be tested in these models. Thus, iPSCs offer an unprecedented opportunity to make rapid progress in the field of stroke and vascular dementia research leading to clinical translation. This review paper summarizes some of the key areas in which patient-derived iPSCs technology has been applied to disease modelling and discusses the ongoing challenges and the future directions for the application of this technology in the field of stroke research.

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Section: Current and Potential Applications Of Human Ipscs In Functio...mentioning

confidence: 99%

Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants

Granata

2023

BMC Cardiovasc Disord

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“…In particular, cells from the central nervous system are difficult to obtain by biopsy; therefore, iPSCs can be useful for disease modeling. Many reports have shown that disease modeling is successful when using iPSCs, including Alzheimer’s disease (AD) [ 23 , 24 ], Parkinson’s disease [ 25 , 26 ], amyotrophic lateral sclerosis (ALS) [ 27 , 28 ], and schizophrenia [ 29 , 30 ]. In addition to diseases involving heart and nerve cells, diseases in most organs can be modeled using disease-specific iPSC technology.…”

Section: Patient-specific Ipscsmentioning

confidence: 99%

Induced Pluripotent Stem Cell-Based Drug Screening by Use of Artificial Intelligence

2022

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Induced pluripotent stem cells (iPSCs) are terminally differentiated somatic cells that differentiate into various cell types. iPSCs are expected to be used for disease modeling and for developing novel treatments because differentiated cells from iPSCs can recapitulate the cellular pathology of patients with genetic mutations. However, a barrier to using iPSCs for comprehensive drug screening is the difficulty of evaluating their pathophysiology. Recently, the accuracy of image analysis has dramatically improved with the development of artificial intelligence (AI) technology. In the field of cell biology, it has become possible to estimate cell types and states by examining cellular morphology obtained from simple microscopic images. AI can evaluate disease-specific phenotypes of iPS-derived cells from label-free microscopic images; thus, AI can be utilized for disease-specific drug screening using iPSCs. In addition to image analysis, various AI-based methods can be applied to drug development, including phenotype prediction by analyzing genomic data and virtual screening by analyzing structural formulas and protein–protein interactions of compounds. In the future, combining AI methods may rapidly accelerate drug discovery using iPSCs. In this review, we explain the details of AI technology and the application of AI for iPSC-based drug screening.

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“…For iPSCs-ALS-MNs, the application of computational techniques such as integrated multi-omic analysis resulted in the identification of novel and known aberrant cellular pathways (Li et al, 2021). Integrated multi-omic analysis distinguished pathogenic versus compensatory disease phenotype pathways, which allows for clearer understanding of disease mechanisms.…”

Section: The Role Of Bioinformatics Perspectives and Futurementioning

confidence: 99%

Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis

Amorós

Choi

Cofré

et al. 2022

Front. Cell Dev. Biol.

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The development of cell culture models that recapitulate the etiology and features of nervous system diseases is central to the discovery of new drugs and their translation onto therapies. Neuronal tissues are inaccessible due to skeletal constraints and the invasiveness of the procedure to obtain them. Thus, the emergence of induced pluripotent stem cell (iPSC) technology offers the opportunity to model different neuronal pathologies. Our focus centers on iPSCs derived from amyotrophic lateral sclerosis (ALS) patients, whose pathology remains in urgent need of new drugs and treatment. In this sense, we aim to revise the process to obtain motor neurons derived iPSCs (iPSC-MNs) from patients with ALS as a drug screening model, review current 3D-models and offer a perspective on bioinformatics as a powerful tool that can aid in the progress of finding new pharmacological treatments.

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An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Cited by 34 publications

References 126 publications

Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants

Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants

Induced Pluripotent Stem Cell-Based Drug Screening by Use of Artificial Intelligence

Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis

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