Several compounds already approved by the U.S. Food and Drug Administration (FDA) can increase the expression of the KCC2 protein in nerve cells, easing motor and respiratory symptoms in a mouse model of Rett syndrome.
The study, “Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice,” was published in the journal Science Translational Medicine.
The KCC2 protein is a neuron-specific membrane protein expressed throughout the central nervous system (brain and spinal cord) and an important regulator of excitatory and inhibitory activities of brain nerve cells (neurons).
Excitatory signaling from one nerve cell to the next makes the receiving cell more likely to fire an electrical signal; inhibitory signaling makes the receiving cell less likely to fire. This is the basis of communication between nerve cells in the brain.
More specifically, the KCC2 protein is responsible for transporting chloride molecules within neurons, an important step that ensures normal electrical activity and communication between nerve cells.
Impaired activity or low levels of KCC2 have been linked to several human brain disorders, including epilepsy, schizophrenia, and spinal cord injury. As such, boosting KCC2 levels may represent a viable therapeutic approach to improving neuronal activity in disorders characterized by imbalances in excitatory and inhibitory activities, such as Rett syndrome.
To explore this hypothesis, Whitehead Institute for Biomedical Research researchers and collaborators conducted a large-scale screen to identify small molecule compounds that could efficiently enhance KCC2 production in neurons. They tested more than 900 chemical compounds in stem cells engineered to quickly report KCC2 levels increase though the activity of a sensitive bioluminescent enzyme.
Several compounds were identified as KCC2 modulators, resulting in more than two-fold increase in the enzyme reporter activity. Among them were KW-2449 and BIO, two compounds that have FDA-approved analog medicines, including the anti-cancer therapy Sutent (sunitinib). Resveratrol, an antioxidant compound derived from plants and found in highest levels in red wine and the skin of red grapes, was also identified. It is not an approved treatment.
Testing them in human neurons, the team confirmed that these compounds could effectively and in a dose-dependent manner increase KCC2 levels.
Further experiments confirmed that treatment with KCC2 enhancers resulted in better neuronal activity and supported nerve cell polarization, required for proper cell-to-cell communication, in immature neurons and brain cells collected from Rett patients.
Researchers next evaluated the impact of treatment with KCC2 enhancers in a mouse model of Rett syndrome — which carry mutated versions of the MeCP2 gene that causes the disease. Mice treated with the experimental compounds showed significantly lower frequency of breathing pauses and were more mobile compared with those given an inactive placebo.
These findings demonstrate that treatment with KCC2 enhancing compounds “ameliorates disease-related behavioral pathologies in MeCP2 mutant mice, consistent with their therapeutic potential,” the researchers wrote.
“The small-molecule compounds described in our study may have therapeutic effects not only in [Rett] but also in other neurological disorders involving dysregulation of KCC2,” the team concluded.