New drug target for Rett syndrome identified

In a paper published on Jan. 4, 2016, in the online Early Edition of the journal Proceedings of the National Academy of Sciences, researchers from Penn State University reports on the discovery of a novel drug target, which could help in the treatment for Rett Syndrome and other forms of autism-spectrum disorders.

In this work, the researchers demonstrate that human neurons derived from induced pluripotent stem cells (iPSCs) from patients with Rett syndrome (Rett neurons), show a significant deficit in neuron-specific K+-Cl− cotransporter2 (KCC2) expression, leading to an impaired GABA functional switch from excitation to inhibition. Restoring KCC2 level rescued GABA functional deficits in Rett neurons.

They also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the Rett syndrome in humans.
Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviour.

Tang and colleagues in this study further demonstrate that MeCP2 regulates KCC2 expression through inhibiting RE1-silencing transcriptional factor REST, a neuronal gene repressor, suggesting a potential therapeutic approach for the treatment of Rett syndrome through modulation of KCC2.

These findings open up the possibility of identifying more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders.

The research was led by Gong Chen, professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State. In addition, the research team also includes Xin Tang , Julie Kim, Li Zhou, Lei Zhang, and Zheng Wu at Penn State; Eric Wengert at Bucknell University; Carol Marchetto and Fred Gage at the Salk Institute for Biological Studies; and Cassiano Carromeu and Alysson Muotri at the University of California - San Diego.

The research was funded by grants from National Institutes of Health (MH083911 and AG045656) and a Stem Cell Fund from the Penn State Eberly College of Science.

Citation: Xin Tang, Julie Kim, Li Zhou, Eric Wengert, Lei Zhang, Zheng Wu, Cassiano Carromeu, Alysson R. Muotri, Maria C. N. Marchetto, Fred H. Gage, and Gong Chen. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. PNAS 2016 ; published ahead of print January 5, 2016, doi:10.1073/pnas.1524013113

Cover image: Composite image of a human nerve cell derived from a patient with Rett syndrome showing significantly decreased levels of KCC2 compared to a control cell. Image courtesy: Gong Chen lab, Penn State University