Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids

EMBO Mol Med. 2021 Jan 11;13(1):e12523. doi: 10.15252/emmm.202012523. Epub 2020 Dec 8.

Abstract

Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.

Keywords: MECP2 mosaicism; cortical organoids; drug discovery; neurodevelopmental disease modeling; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Female
  • Gene Knockout Techniques
  • Humans
  • Methyl-CpG-Binding Protein 2 / genetics
  • Neurons / drug effects*
  • Organoids* / drug effects
  • Phenotype
  • Pyrrolidinones / pharmacology*
  • Quinuclidines / pharmacology*
  • Rett Syndrome* / genetics

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Methyl-CpG-Binding Protein 2
  • N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide
  • Pyrrolidinones
  • Quinuclidines
  • nefiracetam

Associated data

  • GEO/GSE160146