Proteome Sciences presented data this week at the Alzheimer's Association International Conference in Boston demonstrating that treatment with its casein kinase 1 delta inhibitor compounds improved cognition in a mouse model of tauopathy.
The company also demonstrated that treatment with the compounds leads to a reduction of tau deposits and tau phosphorylation in these mouse models, marking a step forward for its CK1d inhibitor program in Alzheimer's.
The firm is now pursuing a pharma partnership deal through which it aims to further develop the program, COO Ian Pike told ProteoMonitor.
Primarily focused on protein biomarker and mass spec research, Proteome Sciences entered the drug development space through a collaboration with researchers at King's College London's Institute of Psychiatry investigating phosphorylation of human tau.
"We had applied mass spectrometry to the analysis of aggregated tau from human brains," Pike said, noting that in this work the company and its IoP collaborators identified 37 different tau phosphorylation sites, including roughly 12 not previously reported.
The researchers followed up this work by investigating these phosphorylation sites, using recombinant tau and kinases in vitro to recreate the various phosphorylation events. Via this work, they identified CK1d as a key player in the hyper-phosphorylation of tau characteristic of Alzheimer's disease.
"It was from that that we started thinking that CK1d might be an interesting drug target," Pike said. "And then we thought, 'Well, if we want to prove that our mass spec method can identify targets that can be drugged, we should at least go through the first phase of developing compounds against those targets to show that they can modulate the process.'"
With that goal in mind, Proteome Sciences embarked on what Pike called a "relatively low-cost design process," by which they developed two CK1d inhibitors – currently the lead compounds in the company's Alzheimer's drug program.
In August 2012, the company presented data demonstrating that the inhibitors lowered tau phosphorylation levels in a human neuronal cell line model (PM 8/10/2012). The data presented at the AAIC meeting this week was the first of the compounds in animal models.
In the study, groups of 12 C57BL/6 mice aged 8.5 months and expressing a double mutant form of human tau were given oral doses of the two CK1d inhibitors twice daily for 8 weeks. On days 50 through 54, the mice were tested for cognitive function using the Morris Water Maze and then sacrificed on day 56, whereupon the researchers measured levels of total tau and phosphorylated tau using Western blotting and selected-reaction monitoring mass spec.
According to Proteome Sciences, treatment with the compounds resulted in statistically significant improvements in mouse cognition. The study also found that treatment resulted in a "marked decrease in the level of CK1d expressed in the brain of treated mice," the researchers wrote. Additionally, they found a reduction in the amount of various phosphorylated forms of tau in hippocampal samples from mice treated with the compounds.
As the majority of these forms are not directly phosphorylated by CK1d, the findings suggest that the inhibitors are functioning through multiple modes, with the inhibition of CK1d affecting the subsequent phosphorylation of tau by kinases such as GSK3b, the researchers noted.
Much of Alzheimer's drug development has focused on attacking the amyloid plaques characteristic of the disease. Pharma firms pursuing this approach, however, have met with little success. For instance, in 2011, Eli Lilly halted late-stage development of a compound called semagacestat after studies showed it actually made patients worse and was associated with an increased risk of skin cancer. Prior to that, in March 2010, Pfizer announced that its Alzheimer's drug Dimebon appeared to be no better than a placebo at treating the disease.
Given such failures, the industry has grown more interested in looking at tau as a potential target, Pike said, noting that this bodes well for Proteome Sciences' aim of inking a pharma partnership deal for development of its CK1d inhibitors.
"All the pharma companies that are still interested in Alzheimer's have either initiated tau programs or are looking to initiate [them]," he said.
Current hypotheses regarding the role of tau in Alzheimer's hold that while tau pathology is a normal aging process, it can also be triggered by stress events such as the aggregation of amyloid-β characteristic of Alzheimer's disease.
This, Pike said, "sets up a cascade of the release of tau from microtubules, sequential tau phosphorylation, and the formation of soluble oligomers which can then transmit across synapses from an affected neuron to a non-affected neuron."
This results in "an autocatalytic cycle with these bad tau oligomers which leads to the accumulation of more and more hyperphosphorylated tau," he said, noting that this model suggests that targeting both tau and Aβ will be required for successful treatment of Alzheimer's.
Exactly how Proteome Sciences takes its compounds forward will depend on the pharma firms it ultimately partners with on the program, Pike said. In the meantime, he said, the company will likely continue to explore the underlying mechanisms with its King's College partners.
"There is a whole bunch more biology that can be done," he said.
Intellectual property for the screening methods used for the initial tau phosphorylation analysis is held jointly by Proteome Sciences and King's College London, Pike said. IP covering the CK1d inhibitors is held solely by Proteome Sciences.