KW-2449 and VPA exert therapeutic effects on human neurons and cerebral organoids derived from MECP2-null hESCs

Abstract

Background Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MECP2), is one of the most prevalent neurodevelopmental disorders in girls. However, the underlying mechanism of MECP2 remains largely unknown and currently there is no effective treatment available for RTT. Methods We generated MECP2-KO human embryonic stem cells (hESCs), and differentiated them into neurons and cerebral organoids to investigate phenotypes of MECP2 loss-of-function, potential therapeutic agents, and the underlying mechanism by transcriptome sequencing. Results We found that MECP2 deletion caused reduced number of hESCs-derived neurons and simplified dendritic morphology. Moreover, MECP2-KO cortical organoids exhibited fewer neural progenitor cells and neurons at day 60. Electrophysiological recordings showed that MECP2 deletion altered synaptic activity in organoids. Transcriptome analysis of organoids identified many genes in the PI3K-AKT pathway downregulated following MECP2 deletion. Treatment with either KW-2449 or VPA, small molecules for the activation of PI3K-AKT signaling pathway, alleviated neuronal deficits and transcriptome changes in MECP2-KO human neuronal models. Conclusions These findings suggest that KW-2449 and VPA might be promising drugs for RTT treatment.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons

“…Some of the compounds identi ed as our top six neuroprotective hits from the iPSC-motor neuron screen against vincristine-induced growth arrest have previously been identi ed as neuroprotective or pro-regenerative. For example, KW-2449 ameliorates Rett's Syndrome disease pathology in mice [32] as well as human-derived neuronal and organoid models of that disease [33]. Despite their use in anticancer therapy, glesatinib, and pelitinib regulate the expression of neuroprotective miRNA as detected in a large screen of human stem cell-induced neurons [34].Blebbistatin is a non-muscle myosin inhibitor that promotes neuronal outgrowth on inhibitory extracellular substrates [35], [36].…”

MeCP2 dysfunction prevents proper BMP signaling and neural progenitor expansion in brain organoid

“…Intriguingly, a recent study demonstrates that MeCP2‐null brain organoids exhibited defects of radial glial cells in neural rosettes at Day 60, but did not show NPC abnormalities at Day 30. 84 However, it should be noted that these organoids were cultured with matrigel, an extracellular matrix (ECM)‐based hydrogel capable of providing ECM signals to organoids for precise development of brain organoids. 85 It has been well‐known that laminin, a major component of matrigel, significantly promotes the NPC proliferation, as well as neurogenesis and neurite outgrowth.…”

Modulation of neuronal activity in cortical organoids with bioelectronic delivery of ions and neurotransmitters

“… 1 , 2 Several efforts have tried to understand the emergence, development, and maturation of circuit formation in these microphysiological systems. 3 , 4 , 5 , 6 Moreover, circuit activity manipulation by either grafting of defined cell types 7 , 8 or treatment with small molecules 9 , 10 has shed new light on the molecular and cellular mechanisms of neurodevelopmental disorders. During development, neuronal activity plays a key role in cortical circuit establishment and maturation.…”