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Human Amyotrophic Lateral Sclerosis Excitability Phenotype Screen: Target Discovery and Validation

30 Pages Posted: 26 May 2020 Sneak Peek Status: Under Review

See all articles by Xuan Huang

Xuan Huang

Harvard University - F.M. Kirby Neurobiology Center

Kasper C.D. Roet

Harvard University - F.M. Kirby Neurobiology Center

Liying Zhang

Pfizer, Inc. - Medicine Design

Amy Brault

Pfizer, Inc. - Medicine Design

Allison P. Berg

Pfizer, Inc. - Rare Diseases Research

Anne B. Jefferson

Pfizer, Inc. - Centers for Therapeutic Innovation (CTI)

Jackie Klug-McLeod

Pfizer, Inc. - Medicine Design

Karen L. Leach

Pfizer Centers for Therapeutic Innovation (CTI)

Fabien Vincent

Pfizer, Inc. - Medicine Design

Hongying Yang

Pfizer Centers for Therapeutic Innovation (CTI)

Anthony J. Coyle

Pfizer Centers for Therapeutic Innovation (CTI)

Devlin Frost

Harvard University - F.M. Kirby Neurobiology Center

Ole Wiskow

Harvard University - Department of Stem Cell and Regenerative Biology

Kuchuan Chen

Harvard University - F.M. Kirby Neurobiology Center

Rie Maeda

Harvard University - F.M. Kirby Neurobiology Center

Alyssa Grantham

Harvard University - F.M. Kirby Neurobiology Center

Mary K. Dornon

Harvard University - F.M. Kirby Neurobiology Center

Joseph R. Klim

Harvard University - Department of Stem Cell and Regenerative Biology

Dongyi Zhao

Harvard University - F.M. Kirby Neurobiology Center

Seungkyu Lee

Harvard University - F.M. Kirby Neurobiology Center

Kevin Eggan

Harvard University - Department of Stem Cell and Regenerative Biology

Clifford J. Woolf

Children's Hospital Boston - F.M. Kirby Neurobiology Center

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Abstract

Drug development is hampered by poor target selection. Phenotypic screens using cells differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature of amyotrophic lateral sclerosis (ALS), we designed a multi-step screening funnel using patient-derived motor neurons. High content live cell imaging was used to evaluate neuronal excitability, and from a chemogenomic library of 2899 target-annotated compounds, 67 reduced hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation, without cytotoxicity. Bioinformatic deconvolution identified thirteen targets that modulate motor neuron excitability, including two known ALS excitability modulators; AMPA receptors and Kv7.2/3 ion channels, constituting target validation. We also identified D2 dopamine receptors as contributing to ALS motor neuron excitability, a novel discovery. This screen demonstrates the power of human disease cell based phenotypic screens for identifying clinically relevant targets for neurological disorders.

Keywords: ALS, hyperexcitability, phenotypic screen, high throughput, high content, AMPA, Kv7, D2 receptor

Suggested Citation

Huang, Xuan and Roet, Kasper C.D. and Zhang, Liying and Brault, Amy and Berg, Allison P. and Jefferson, Anne B. and Klug-McLeod, Jackie and Leach, Karen L. and Vincent, Fabien and Yang, Hongying and Coyle, Anthony J. and Frost, Devlin and Wiskow, Ole and Chen, Kuchuan and Maeda, Rie and Grantham, Alyssa and Dornon, Mary K. and Klim, Joseph R. and Zhao, Dongyi and Lee, Seungkyu and Eggan, Kevin and Woolf, Clifford J., Human Amyotrophic Lateral Sclerosis Excitability Phenotype Screen: Target Discovery and Validation. Available at SSRN: https://ssrn.com/abstract=3596591 or http://dx.doi.org/10.2139/ssrn.3596591
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Xuan Huang

Harvard University - F.M. Kirby Neurobiology Center

United States

Kasper C.D. Roet

Harvard University - F.M. Kirby Neurobiology Center

United States

Liying Zhang

Pfizer, Inc. - Medicine Design

235 East 42 Street
New York, NY 10017
United States

Amy Brault

Pfizer, Inc. - Medicine Design

235 East 42 Street
New York, NY 10017
United States

Allison P. Berg

Pfizer, Inc. - Rare Diseases Research

235 East 42 Street
New York, NY 10017
United States

Anne B. Jefferson

Pfizer, Inc. - Centers for Therapeutic Innovation (CTI)

235 East 42 Street
New York, NY 10017
United States

Jackie Klug-McLeod

Pfizer, Inc. - Medicine Design

235 East 42 Street
New York, NY 10017
United States

Karen L. Leach

Pfizer Centers for Therapeutic Innovation (CTI)

Fabien Vincent

Pfizer, Inc. - Medicine Design

235 East 42 Street
New York, NY 10017
United States

Hongying Yang

Pfizer Centers for Therapeutic Innovation (CTI)

Anthony J. Coyle

Pfizer Centers for Therapeutic Innovation (CTI)

Devlin Frost

Harvard University - F.M. Kirby Neurobiology Center

United States

Ole Wiskow

Harvard University - Department of Stem Cell and Regenerative Biology

7 Divinity Avenue
Cambridge, MA 02138
United States

Kuchuan Chen

Harvard University - F.M. Kirby Neurobiology Center

United States

Rie Maeda

Harvard University - F.M. Kirby Neurobiology Center

United States

Alyssa Grantham

Harvard University - F.M. Kirby Neurobiology Center

United States

Mary K. Dornon

Harvard University - F.M. Kirby Neurobiology Center

United States

Joseph R. Klim

Harvard University - Department of Stem Cell and Regenerative Biology

7 Divinity Avenue
Cambridge, MA 02138
United States

Dongyi Zhao

Harvard University - F.M. Kirby Neurobiology Center

United States

Seungkyu Lee

Harvard University - F.M. Kirby Neurobiology Center

United States

Kevin Eggan

Harvard University - Department of Stem Cell and Regenerative Biology

7 Divinity Avenue
Cambridge, MA 02138
United States

Clifford J. Woolf (Contact Author)

Children's Hospital Boston - F.M. Kirby Neurobiology Center ( email )

United States

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