ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neurodegeneration
This article is part of the Research TopicAdvances in Neurodevelopmental and Neurodegenerative Disease Research: Focus on Innovative Human-Relevant Brain ResearchView all 10 articles
An induced pluripotent stem cell-based chemical genetic approach for studying spinal muscular atrophy
Provisionally accepted
Richard Giadone1,2,3,4
Kristina Holton1,2,3,4
Xiaoyu Hu1,4
Ted Natoli2,3Sabrina Ghosh1,4Stanley Gill2,4,5Aravind Subramanian2,3
Lee L Rubin1,2,3,4*- 1Department of Stem Cell and Regenerative Biology, Faculty of Arts and Sciences, Harvard University, Cambridge, United States
- 2Broad Institute, Cambridge, United States
- 3Broad Institute Stanley Center for Psychiatric Research, Cambridge, United States
- 4Harvard Stem Cell Institute, Cambridge, United States
- 5Harvard University Department of Stem Cell and Regenerative Biology, Cambridge, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Spinal muscular atrophy (SMA) is a genetic disease characterized by degeneration of spinal cord motor neurons and neuromuscular junctions. Despite recent development in therapies for SMA, treatment efficacy largely relies on administration of drugs early in disease progression and is impacted by underlying patient genetics. Drug discovery for other diseases of the central nervous system (CNS) has also been hindered by heterogeneity in patient genetics and clinical presentations, as well as the need for early intervention. To address these hurdles, we utilized a chemical genetic-based screening approach to adapt the Connectivity Map (CMAP)/L1000 platform to study SMA. To do this, we differentiated moderate and severe SMA patient-specific induced pluripotent stem cells into neuronal cells utilizing a forward programming differentiation protocol, exposed each to 360 neuroactive or CNS disease-related compounds, and interrogated resulting changes in expression of >400 neural genes in a platform we term CMAPneuro. In doing so, we generated 4,559 transcriptional profiles identifying stimuli that modulate gene expression differences across SMA neurons. Finally, we make these data queryable, allowing the research community to 1.) identify CNS disease-related perturbagens that mimic or reverse differentially expressed genes, or 2.) explore the transcriptional response of a given perturbation in diverse SMA neuronal cells. Taken together, CMAPneuro represents a novel tool to identify candidate stimuli for follow-up investigation into the biology of SMA and related disorders.
Keywords: spinal muscular atrophy (SMA), Connectivity Map (CMap), L1000, iPSCs, chemicalgenetic screening
Received: 29 Aug 2025; Accepted: 18 Nov 2025.
Copyright: © 2025 Giadone, Holton, Hu, Natoli, Ghosh, Gill, Subramanian and Rubin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lee L Rubin, lee_rubin@harvard.edu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.