Stem Cell 'Mini Brains' Developed to Reveal Potential Drug Treatment for Rare Disorder

MECP2 duplication syndrome is caused by duplication of genetic material in a specific region of the X chromosome.

Dysfunctional cells may be able to be rescued by suppressing a critical genetic alteration through the use of “mini-brains” built with induced pluripotent stem cells derived from patients with a rare neurological disorder, according to a new study.

Researchers at the University of California, San Diego School of Medicine published their findings in the online issue of Molecular Psychiatry.

The neurological disorder is called MECP2 duplication syndrome. The disorder was first described in 2005 and is caused by duplication of genetic material in a specific region of the X chromosome that encompasses MECP2 and adjacent genes.

Symptoms of the disease include low muscle tone, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, autistic behaviors, and potentially severe intellectual disability.

The disorder is inherited but can also occur randomly. It occurs in almost exclusively males.

A similar disorder known as Rett (RTT) Syndrome that involves MECP2 gene deletions primarily affects females. Current treatment is based on patient symptoms with therapies, drugs and surgeries to address specific issues as they arise.

As was done in previous studies, researchers in the current study took skin cells from MECP2 duplication patients, converted them into induced pluripotent stem cells (iPSC), then programmed the stem cells to become neurons that recapitulate the disorder more robustly than existing mouse models.

Alysson Muotri, PhD, associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine, said analyses of the iPSC-derived neurons revealed novel molecular and cellular phenotypes, including an over-synchronization of the neuronal networks.

Contrary to previous reports for Rett syndrome, these phenotypes go in the opposite direction, suggesting that correct gene dosage is important for homeostasis in human neurons. Importantly, noted Muotri, the finding with human neurons helped direct a drug screening that yielded a drug candidate, a histone deacetylase inhibitor that reversed all the MECP2 alterations in the mutant neurons, with no harm to control neurons.

“This work is encouraging for several reason,” Muotri said. “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.”

The findings further underscore the potential of stem cell-based models as an efficient method for screening potential drug libraries for the ability to rescue human neuronal phenotypes in a dish. The research team will be concluding its preclinical studies in preparation for moving into clinical trials as soon as possible.