A Novel Approach for the Treatment of Alzheimer’s Disease

BACKGROUND 

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 

• Treatment and prevention of 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-β-amyloid therapeutic target for AD.
• Acts on early and late stages of AD, indicating the potential to prevent and rescue disease progression.
• Safety of racemic carvedilol mixture has been proven – safety of R-carvedilol enantiomer will be easier to get accepted.

PUBLICATIONS AND RESOURCES 

• PCT publication: WO2022126236A1
• Journal publication: Yao J et al. (2020). Limiting RyR2 open time prevents Alzheimer’s Disease-related neuronal hyperactivity and memory loss but not β-amyloid accumulation. Cell Reports
• The Gauntlet news article: A tale of transgenic mice: Heart failure medication might prevent, and reverse Alzhimer’s Disease.
• Co-lead researcher profile: Wayne Chen
• Co-lead researcher profile: Thomas Back