A novel means of modeling a rare but devastating neurological disorder has helped scientists identify a potential drug treatment, a compound that can act on epigenetic pathways to suppress a critical genetic alteration. Scientists have managed this feat through the use of “mini-brains.” Derived from induced pluripotent stem cells, these mini-brains recapitulated MECP2 duplication syndrome. The mini-brains also served as a drug-screening platform. Ultimately, the mini-brains helped identify a histone deacetylase inhibitor that could reverse the build-up of excess MECP2 that is associated with MECP2 duplication syndrome, and thereby rescue dysfunctional cells.

MECP2 duplication syndrome displays a wide variety of symptoms, among them low muscle tone, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, autistic behaviors, and potentially severe intellectual disability. First described in 2005, the disorder is caused by duplication of genetic material in a specific region of the X chromosome that encompasses MECP2 and adjacent genes.

To model the disorder and hopefully reveal new treatment strategies, researchers at the University of California, San Diego took skin cells from MECP2 duplication patients, converted them into induced pluripotent stem cells (iPSCs), and then programmed the stem cells to become neurons that recapitulated the disorder.

This work was undertaken by researchers led by Alysson Muotri, Ph.D., an associate professor of pediatrics and cellular and molecular medicine. It led to the creation of mini-brains that not only modeled MECP2 duplication, but also showed the effects of different duplication sizes. Thus, Dr. Muotri’s team was able to evaluate the impact of increased MCP2 (methyl-CpG-binding protein-2) dosage in human neurons. Dr. Muotri’s team also found that their mini-brains recapitulated MECP2 duplication syndrome more robustly than existing mouse models.

These developments were reported September 8 in the journal Molecular Psychiatry, in an article entitled, “Altered neuronal network and rescue in a human MECP2 duplication model.” This article detailed how the iPSC-derived neurons revealed novel molecular and cellular phenotypes.

“We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity,” wrote the authors. “In addition, using multi-electrode arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons.”

Having characterized to their satisfaction, Dr. Muotri and colleagues proceeded to their study’s next phase, a drug-screening effort. They succeeded in uncovering a drug candidate that reversed all the MECP2 alterations in the mutant neurons, with no harm to control neurons.

“One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate,” the authors indicated. “Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders.”

The identification of a promising drug candidate is especially welcome given that current treatment for MECP2 duplication syndrome is largely symptomatic, involving therapies, drugs, and surgeries that address specific issues.

“This work is encouraging for several reasons,” explained Dr. Muotri. “First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.”

Dr. Muotri noted that his team’s findings underscore the potential of stem cell-based models of severe neurodevelopmental disorders. Besides recapitulating early developmental problems, these models can efficiently screen potential drug libraries. Using such cellular tools, researchers can readily assess drugs’ abilities to rescue human neuronal phenotypes in a dish. Dr. Muotri added that his team would expedite its preclinical studies and move into clinical trials as soon as possible.