James Barrow (Lieber Institute for Brain Development)
Jingbo Xiao (NCATS)
Marc Ferrer-Alegre (NCATS)
Michael Poslusney (Lieber Institute for Brain Development)
Noel Southall (NCATS)
Steven Titus (NCATS)
Wei Zheng (NCATS)
This technology includes compounds, pharmaceutical compositions and methods of treating or preventing neurological or psychiatric disorders for which inhibiting KCNH2-3.1 containing potassium channels provides a therapeutic effect. Polymorphisms in the KCNH2 gene have been associated with altered cognitive function and schizophrenia. The KCNH2 gene encodes the protein which forms the human ether-a-go-go related (hERG) voltage-gated potassium channel 4, 5. The risk-associated alleles predict impaired cognitive function in both patients and healthy controls as well as overexpression of KCNH2-3.1, a truncated isoform with unique electrophysiological properties. KCNH2-3.1 is a primate-specific isoform, enriched in the brain, which lacks the PAS domain critical for the slow-deactivation properties of hERG channels. ERG channels have been shown to regulate the activity of neurons in multiple brain regions, suggesting a possible cause of the cognitive dysfunction in patients with schizophrenia associated with elevated KCNH2-3.1 may be decreased synchrony among functionally connected neurons. Those with overexpression of KCNH2-3.1 exhibit more inefficient neuronal processing in the hippocampus and frontal cortex during memory tasks as measured with fMRI1.
Treatment and prevention of schizophrenia and other CNS disorders.
Cognitive dysfunction associated with schizophrenia is a major unmet therapeutic need.