A Novel Approach for the Treatment of Memory Loss from Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common form of dementia that affects a growing number of individuals every year. Despite significant efforts, there is currently no effective treatment for AD. Dr. Wayne Chen and Dr. Thomas Back at the University of Calgary have developed a novel approach for treating AD by targeting neuronal hyperactivity through limiting the open duration of ryanodine receptor 2 (RyR2), which is a well-known regulator of neuronal excitability. Genetically reducing RyR2 open time prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe, early-onset AD mouse model. Pharmacologically limiting RyR2 open time with the R-carvedilol enantiomer (but not racemic carvedilol) with a safety dosage also prevents and rescues neuronal hyperactivity, learning and memory impairments, and neuron loss even in the late stages of AD. Importantly, these AD-related deficits were prevented even with continued β-amyloid accumulation. Thus, limiting RyR2 open time may offer a hyperactivity-directed, non-β-amyloid-targeted, strategy for treating AD. The inventors have designed and synthesized a group of R-carvedilol analogs which have been tested in preliminary cell-based assays.  

AREAS OF APPLICATION: 

• Alzheimer’s Disease 
• Other potential areas of application include diseases with symptoms associated with neuronal hyperactivity, including Parkinson’s Disease and epilepsy  

COMPETITIVE ADVANTAGES: 

• Potential to lead to a novel, non-amyloid therapeutic target for AD 
• Safety of racemic Carvedilol mixture has been proved, therefore safety of R-carvedilol enantiomer would be easier to get accepted. 

STAGE OF DEVELOPMENT 

• Pre-clinical: some in vitro and in vivo tests have been carried out 
• Seeking a partnership for further pre-clinical validation of compounds   

ADDITIONAL INFORMATION: 

•  PCT applications filed 
• Publication: Yao J, Sun B, Institoris A, et al. Limiting RyR2 Open Time Prevents Alzheimer’s Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation. Cell Rep. 2020;32(12):108169. 
• The Gauntlet news article: A tale of transgenic mice: heart medication might prevent, and reverse Alzheimer’s Disease 
• Researcher profile: Dr. Wayne Chen  
• Researcher profile: Dr. Thomas Back