Authors: Yunhee Kang, Ying Zhou, Yujing Li, Yanfei Han, Jie Xu, Weibo Niu, Ziyi Li, Shiying Liu, Hao Feng, Wen Huang, Ranhui Duan, Tianmin Xu, Nisha Raj, Feiran Zhang, Juan Dou, Chongchong Xu, Hao Wu, Gary J. Bassell, Stephen T. Warren, Emily G. Allen, Peng Jin & Zhexing Wen


The Fragile X mouse model has been essential to treatment development for many years in Fragile X. Unfortunately, treating the mouse has not always translated well into treating humans. A study team lead by Emory University researchers may have a solution.

The study team used patient-derived induced pluripotent stem cells (iPSCs) to create Fragile X syndrome forebrain organoids. This forebrain organoid model matches molecular and pharmacological aspects of Fragile X syndrome more closely than mouse versions. Using reprogrammed skin cells donated by patients with Fragile X syndrome, the study team was able to mimic early stages of brain development in these cells cultivated in a dish. Don’t worry — the organoids are not considered conscious!

Compared with control organoids, the Fragile X organoids undergo accelerated differentiation (the process of one cell type changing to another cell type) and had fewer neurons that send inhibitory signals. Inhibitory neurons release GABA, which is important for regulating emotions, helping us from becoming overwhelmed in stressful situations. With fewer inhibitory neurons, individuals with Fragile X syndrome (and these iPSCs) have less GABA, resulting in less emotional regulation and more overstimulation. The Fragile X organoid neurons were also hyperexcitable, meaning they arranged themselves quickly and moved in disorganized patterns. The various analyses conducted by the study team showed that the loss of the Fragile X protein, FMRP, altered gene expression in a cell-type-specific manner. This means that each cell type is changed differently from the lack of FMRP depending on the cell type. The loss of the FMR1 gene also altered the activity of other genes in the brain organoid in comparison to the mouse, suggesting that the Fragile X syndrome brain organoid may be more sensitive.

These differences between the models could explain why trials in Fragile X syndrome have failed in the past. The study team tested two PI3 kinase inhibitor compounds, compounds that are being considered for clinical trials — on the brain organoids. These compounds seemed to make the Fragile X syndrome brain organoids function more like the control organoids. The study team thinks that the Fragile X syndrome brain organoids can not only test potential compounds for treatment but lead to new drug targets or new genes to target with treatment. Given the large number of genes affected by the loss of FMRP, targeting one of those genes for treatment could help with overall treatment of Fragile X syndrome.

Why This Matters

We have had several failed trials in Fragile X syndrome, and no treatment specific to Fragile X syndrome. While there is promise for future treatments, utilizing this iPSC brain organoid model for future treatment development could prove to be successful. Because the Fragile X syndrome brain organoid seems to be sensitive and better mimic a human with Fragile X syndrome, this model could better find and evaluate new treatments.

Next Steps

Using these brain organoids, the Emory team is trying to further understand the role of FMRP in the context of human brain development. They are systematically testing all the existing therapeutic strategies in brain organoids, and will conduct unbiased drug screening to identify new compounds that could rescue the phenotypes associated with the loss of FMRP in humans.

Acknowledgements and Funding

This work is dedicated to the late S. Warren and was supported, in part, by the National Institutes of Health (NS091859 to S.T.W. and P.J.; HD104458 to S.T.W., P.J., G.B. and Z.W.; HD082013 to G.B.; AI131130 to Z.W. and P.J.; MH123711 and MH121102 to Z.W.; and NS051630 and NS111602 to P.J.), the Department of Defense (W81XWH1910068 to E.G.A. and W81XWH1910353 to Z.W.), the Edward Mallinckrodt Jr. Foundation (Z.W.) and the FRAXA Research Foundation (Y.K.). We would like to thank S. Sloan at Emory University for help with scRNA-seq analyses. This study was supported, in part, by the Emory Integrated Genomics Core, which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. This work was performed with the support of the Georgia Genomics and Bioinformatics Core (GGBC) at the University of Georgia. The scRNA-seq work was performed at the GGBC at the University of Georgia, Athens. We thank M. Alabady and his team at the GGBC for their support and contribution to this work.

Kang, Y., Zhou, Y., Li, Y. et al. A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies. Nat Neurosci 24, 1377–1391 (2021).↗

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Featured image by mcmurryjulie↗ from Pixabay↗