Using three-dimensional “mini-brains” grown from patient-derived induced pluripotent stem cells (iPSCs), researchers at the University of California, San Diego School of Medicine report identifying a drug candidate that can reverse cellular dysfunction in MECP2 duplication syndrome by suppressing a key genetic abnormality.
The study appears in the September 8 online issue of Molecular Psychiatry.
MECP2 duplication syndrome is a rare, severe neurodevelopmental disorder caused by extra copies of genetic material on a segment of the X chromosome that includes the MECP2 gene and nearby genes. Since it was first characterized in 2005, the condition has been associated with a spectrum of symptoms that commonly include hypotonia (low muscle tone), delayed development, recurrent respiratory infections, speech difficulties, seizures, autistic features and significant intellectual disability in many cases.
The syndrome is typically inherited but can also arise from spontaneous genetic changes. It almost exclusively affects males. By contrast, Rett syndrome—another disorder involving the MECP2 gene—results from loss or mutation of MECP2 and is primarily diagnosed in females. Current care for individuals with MECP2 duplication syndrome is largely supportive and symptomatic, focusing on therapies, medications and procedures that treat specific complications.
Building on earlier translational work using human cells to study Rett syndrome, senior author Alysson Muotri, PhD, associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine, and colleagues reprogrammed skin cells from patients with MECP2 duplication syndrome into iPSCs. They then directed those stem cells to differentiate into cortical neurons and neuronal networks that more faithfully reproduce human disease features than many animal models.
Detailed analysis of the patient-derived neurons revealed previously unreported molecular and cellular characteristics. Among the notable findings was exaggerated synchronization across neuronal networks—an over-synchronization that contrasts with the lesser synchronization reported in some studies of Rett neurons. This contrast highlights how precise MECP2 gene dosage is critical for maintaining neuronal balance and network behavior in human cells.
Using these human neuronal cultures as a screening platform, the team evaluated a focused library of compounds known to act on epigenetic regulators, reasoning that MECP2 exerts control at the epigenetic level. From this screen they identified a histone deacetylase (HDAC) inhibitor, designated NCH-51, which reversed the MECP2-related abnormalities observed in the mutant neurons without producing detectable harm to control cells. This agent had not previously been considered for neurological indications.
“This work is encouraging for several reasons,” Muotri said. “First, it points to a compound class not previously explored as a therapeutic option for this disorder. Second, the use of human iPSC-derived neuronal models allowed a rapid, disease-relevant screening process that would have taken much longer and possibly yielded less translatable results if conducted solely in mouse models.”
These results support the growing utility of stem cell-based systems to model human neurodevelopmental disorders and to serve as efficient platforms for drug discovery. The researchers report that they are advancing preclinical studies with the goal of moving toward clinical evaluation as soon as safety and efficacy are adequately established.
Contributing authors on the paper include researchers from institutions in the United States, Belgium, India, Brazil and Italy. The collaborative team comprises scientists with expertise in stem cell biology, neurodevelopment, genetics and pharmacology, reflecting the interdisciplinary approach required to model complex human neurodevelopmental syndromes and to pursue therapeutic candidates.
Funding: Support for the research came from multiple sources, including the California Institute for Regenerative Medicine, the National Institutes of Health (grants 1-DP2-OD006495-01 and R01MH094753), the International Rett Syndrome Foundation, NARSAD, the National Institute of Neurological Disorders and Stroke (grant K08 NS062711), regional research foundations and other nonprofit organizations.
Source: Scott LaFee – UCSD
Image credit: Image adapted from credit to Nissim Benvenisty, Russo E/PLOS Biology (licensed CC BY 2.5)
Original research article: “Altered neuronal network and rescue in a human MECP2 duplication model,” published online September 8, 2015 in Molecular Psychiatry (doi:10.1038/mp.2015.128).
Abstract
Altered neuronal network and rescue in a human MECP2 duplication model
Increased dosage of methyl-CpG-binding protein 2 (MeCP2) produces a profound neurodevelopmental phenotype evident from birth. The investigators generated induced pluripotent stem cells from patients with MECP2 duplication syndrome carrying duplications of varying sizes to examine the effects of elevated MeCP2 dosage in human neurons. Cortical neurons derived from these MECP2 duplication iPSC lines showed increased synapse formation and greater dendritic complexity. Multi-electrode array recordings revealed altered neuronal network synchronization in neurons carrying the duplication. Because MeCP2 functions at the epigenetic level, the team screened a panel of compounds with defined epigenetic activities and identified the histone deacetylase inhibitor NCH-51 as a candidate that reversed the observed neuronal alterations. This human cellular model captures early features of MECP2 duplication syndrome and offers a promising platform for therapeutic drug screening for severe neurodevelopmental disorders.