PITTSBURGH, Nov. 12, 2014 /PRNewswire/ -- Cognition Therapeutics Inc. (CogRx) today announced the publication online of two articles entitled: "Alzheimer's therapeutics targeting Amyloid beta 1-42 oligomers I: Abeta oligomers binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits" and "Alzheimers therapeutics targeting Amyloid beta 1-42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity," in PLOS ONE, the innovative and pioneering peer-reviewed open access science and medicine journal. Together these articles describe the coincident discovery of a major new drug target in the human brain implicated in Alzheimer's disease and a series of investigational drug candidates, which potentially can halt and reverse the insidious and devastating memory loss that Alzheimer's brings.
Sigma-2/PGRMC1 receptor, the new Alzheimer's drug target, mediates the pathological effects of the water-soluble oligomeric version of amyloid beta 1-42 protein (Abeta), the agent widely thought to be a major causative factor of Alzheimer's disease. The first article in PLOS, entitled "Alzheimer's therapeutics targeting Amyloid beta 1-42 oligomers I: Abeta oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits," describes CogRx's Alzheimer's screening platform and proprietary CNS-biased compound library and its discovery of a set of candidate agents that are capable of blocking the toxic effects of both synthetic and human Abeta oligomers on processes important to neuronal cell communication and viability and ultimately memory formation and consolidation. The CogRx compounds prevent Abeta-induced neuronal degeneration in a mouse brain cell culture system and reverse Abeta-induced memory deficits in preclinical rodent models of memory and learning using both normal and APP-Swedish London transgenic mice. In the second article, entitled "Alzheimers therapeutics targeting Amyloid beta 1-42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity," CogRx screened its compounds in industry-standard counterscreening assays to determine which receptors the compounds bound to. Sigma-2/PGRMC1 receptor protein was the only receptor that the compounds bound to with significant affinity, and further studies suggested it to be a major pharmacologically tractable target for Abeta toxicity in human brain.
"Our approach is fundamentally different from that of other therapeutics in development, such as BACE inhibitors and monoclonal antibodies targeting Abeta protein which focus on reducing the levels of Abeta in the brain," says Dr. Susan Catalano, CSO, Cognition Therapeutics. "We discovered that Abeta oligomers bind very specifically and saturably to the sigma-2/PGRMC1 receptor or proteins that are tightly controlled by it. When our compounds bind to sigma-2/PGRMC1 receptors, they alter it so that the oligomers can no longer bind, or are actually kicked off if they are already bound. One of these molecules is our investigational new drug candidate that we hope will be in the clinic next year. This molecule represents the first opportunity to directly test this target together with the hypothesis that soluble toxic Abeta oligomers interact with this receptor on brain's nerve cells to cause memory loss in Alzheimer's disease."
Sigma-2/PGRMC1 plays an important role in controlling whether or not certain proteins that are required for normal memory formation are located on the surface of brain cells. When Abeta builds up in the brain, as can be seen in older humans or Down's syndrome individuals, it forms oligomers that stick to the brain cell synapses and result in the reduction of proteins that are required for normal memory formation. The findings reported here make an important link between these two observations, and suggest that oligomer interactions with sigma-2/PGRMC1 may lead directly to this reduction.
Hank Safferstein, Cognition Therapeutics CEO, commented, "Taken together, the exciting implication of these findings is that the investigational agents we have discovered and are currently developing give the promise of not only reversing the memory and learning defects in patients diagnosed with Alzheimer's disease but also of slowing or even halting disease progression. This would be a quantum leap in mechanism of action from the currently used anti-Alzheimer's agents which are at best only mildly symptom reducing. Disease modification is the Holy Grail of Alzheimer's research and we believe our drugs give new hope of a meaningful and lasting benefit to patients diagnosed with Alzheimer's disease and their caregivers."
Sigma-2/PGRMC1 is a heme binding protein that belongs to the ubiquitous membrane associated progesterone receptor (MAPR) protein family and proposed as a biomarker of cell proliferation and solid tumors. An important property that has bearing on the discoveries described here is that it has been shown to stabilize surface receptor expression of a variety of proteins and receptors and directly associates with proteins involved in cell membrane transport processes. It is widely expressed in the brain at low levels and abundantly in the periphery including the liver and kidneys. There is a developing literature around its putative role in tumorigenesis but it has not been previously linked to Alzheimer's disease.
Historically, the sigma-2 receptor has been known since the 1970's as a putative CNS target for therapy of anxiety, depression, and stroke. It was characterized pharmacologically together with the sigma-1 receptor using radioligand binding studies. However, unlike the sigma-1 receptor, for which the gene sequence and structure is known, the structure of sigma-2 has never been elucidated. This has hampered progress on the understanding of its function but the recent identification that the sigma-2 binding site is part of the progesterone receptor membrane component 1 (PGRMC1) protein has stimulated new impetus in defining its function, the latest results of which are described here.
CogRx, is a drug discovery and development company based in Pittsburgh, PA, specializing in finding new small molecule therapies for neurodegenerative diseases involving proteopathic processes such as Alzheimer's, Parkinson's and Creutzfeld-Jacob's disease. Proteopathies are diseases resulting from the body's natural proteins pathologically changing shape and becoming toxic. Toxic proteins play a crucial role in a large number of human diseases, and there are currently no therapeutics available to prevent toxic protein accumulation or block their destructive effects. CogRx is founded on their unique expertise around novel neurodegenerative disease targets combined with proprietary high content bioassay and medicinal chemistry platforms capable of discovering and delivering high quality candidate compounds into development.
SOURCE Cognition Therapeutics, Inc. (CogRx)