UC Davis researchers found that calcium-activated potassium channel (KCa3.1) is a potential target for treating Alzheimer’s disease. Their preclinical findings, published in Annals of Clinical and Translational Neurology, showed that senicapoc, a KCa3.1 inhibitor, reduced neuroinflammation and mitigated Alzheimer’s disease-like deficits in mice.
“Our study shows that KCa3.1 could be a therapeutic target for Alzheimer’s disease,” said Izumi Maezawa, a MIND Institute researcher and an associate adjunct professor in the Department of Pathology and Laboratory Medicine at UC Davis. “Most significantly, our preclinical data results provide a strong support to repurposing senicapoc for the treatment of Alzheimer’s disease with the advantage of it being ready for clinical trials.”
Senicapoc was initially developed to treat sickle cell anemia. Although it advanced to a Phase-3 clinical trial and was found to be safe and well-tolerated by patients, it was terminated in 2007 for not achieving the anticipated results.
The researchers said that the findings from this study suggest that senicapoc could be repurposed for treatment of Alzheimer’s disease and mild cognitive impairment, potentially eliminating the need for time-consuming and costly work involved in new drug discovery. On average, it takes at least 15 years and $1.5 billion to bring a successful drug to the market.
Microglia are primary immune cells in charge of defending the brain against pathogens and brain injuries through a process called phagocytosis, the clearing of cellular debris and dead neurons from the nerve tissues. When triggered by infection, injury or pathological stimulants (such as Aβ oligomer amyloids in the case of Alzheimer’s disease), microglia become activated and release inflammatory agents that, when in excess, may inadvertently damage the brain.
Prolonged activation of microglia and recurrent inflammation cause neuronal damage and are believed to play a pivotal role in the initiation and progression of Alzheimer’s disease. Maezawa’s group previously found that the microglial activation processes require a ramp-up of KCa3.1 activity. The current preclinical study further found that harmful brain inflammation orchestrated by microglia in a mouse model of Alzheimer’s disease can be curbed by KCa3.1 blockers such as senicapoc.
“Now we are actively working with the clinical team at the UC Davis Alzheimer’s Disease Center to conduct a phase IIb clinical trial of senicapoc,” said Lee-Way Jin, director of neuropathology and professor in the Department of Pathology and Laboratory Medicine.
The preclinical work was supported by a grant from the BrightFocus Foundation (A2013414S), the UC Davis Department of Pathology and Laboratory Medicine, NIH grants R01 AG043788 (NIA), and R01 NS100294 (NINDS). This work was also supported in part by P30 AG10129 (NIA).
Other researchers on this study include Jacopo Di Lucente, Hai M. Nguyen, Vikrant Singh, Latika Singh, Monique Chavez, Trevor Bushong, and Heike Wulff at UC Davis.
The UC Davis Alzheimer’s Disease Center advances understanding of Alzheimer’s disease and related dementias through comprehensive patient evaluations and cutting-edge research. For information, visit http://www.ucdmc.ucdavis.edu/alzheimers/.