Cogrx Alzheimer’s Therapies

 

Alzheimer’s disease is a debilitating neurodegenerative disease and the most common form of dementia. Symptoms include irritability, confusion, mood swings, language difficulties and memory loss. Cognitive dysfunction becomes more pronounced as the disease progresses, leading to the loss of bodily functions and eventually death. AD is characterized by the presence of amyloid plaques in the brain. Soluble beta-amyloid (Abeta) oligomers are thought to underlie the cognitive deficits associated with Alzheimer’s disease. Our first-in-class novel therapies pharmacologically compete with Abeta oligomers for critical receptor targets preventing synapse loss and improving memory. Our small molecule therapeutics act through molecular targets that have not been previously implicated in AD.

Science and Technology

Idea

Cognition Therapeutics was founded on the conviction that drug discovery for neurodegenerative diseases is best served by insightful design of phenotypic, functional screens that can measure complex biological processes relevant to the disease rather than follow the conventional approach of defining a molecular target in isolation though genomics, protein cloning and high throughput screening. It scientists realized that intraneuronal vesicular transport, which is sensitive to Abeta disruption, was a biological system critical to the synaptic plasticity so essential to memory formation and may have value as an unbiased phenotypic screen capable of capturing effects on multiple molecular targets. Such an assay could have good predictability for in vivo efficacy and thereby enhanced potential for drug discovery in Alzheimer’s disease.

Cognition Therapeutics’ scientists have developed this idea into a robust, high content, screening platform using organotypic 3D cultures of hippocampal and cortical neurons to recapitulate the complexity and heterogeneity of these brain structures. They have used this unique primary screen together with other screening strategies to probe the natural chemical scaffolds of their proprietary chemical libraries for activity against the neuronal toxicity of soluble Abeta oligomers believed to contribute to neurodegeneration in Alzheimer’s disease. They have been able to validate a completely new protein drug target for Alzheimer’s disease, the sigma-2/PGRMC1 receptor, which behaves as a saturable binding site for soluble Abeta and mediates its synaptotoxicity (Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. (2014) PLoS ONE 9(11): e111899. doi:10.1371/journal.pone.0111899).

Research

Success

On the back of this cutting-edge research, Cognition Therapeutics has accelerated its drug discovery and development efforts and has identified several drug-like small molecules capable of potently and competitively blocking Abeta binding to sigma-2/PGRMC1 (Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, et al. (2014) PLoS ONE 9(11): e111898. doi:10.1371/journal.pone.0111898). These compounds also both reverse and prevent memory deficits in preclinical models of Abeta toxicity. One candidate, CT1812, has already entered the clinic and is in clinical testing in Alzheimer's disease patients. All in all, Cognition Therapeutics has successfully assembled a world-class team and established breakthrough technology enabling it to discover and develop truly innovative therapies for prevention and treatment of Alzheimer’s and related neurodegenerative diseases.