Development of CDK5-p25 modulator to treat Alzheimer's Disease and Frontotemporal Dementia

Post-mortem evidence shows that CDK5, a major kinase for tau and amyloid precursor protein, is hyperactive in the brains of patients with AD. Multiple genome wide association studies link CDK5 alleles to AD. Elegant genetic mouse(5xFAD) and human stem cell-derived neuron studies demonstrate the CDK5 hyperactivity is required (rather than just a correlation) for progression of AD pathology. CDK5 is widely considered an ideal target for AD therapy because it is only active in neurons, and it acts upstream of tau hyperphosphorylation, amyloid plaque deposition, and inflammation. Accordingly, several major pharma companies targeted CDK5 with kinase inhibitor programs. These companies eventually discontinued their CDK5 programs before reaching the clinic due to off-target toxicity. CDK5 hyperactivity was mediated by its interaction with p25, a cleavage product of p35 which is uniquely expressed in the brain. Dr. Harish Pant of NINDS, the original discoverer of CDK5 activity, circumvented this problem, using an unprecedented approach to kinase pharmacobiology. Rather than developing a kinase inhibitor, Dr. Pant developed and patented TFP5, a 34 amino acid peptide therapeutic that disrupts CDK5-p25 interaction in the brain, blocking toxic hyperactivity while preserving normal levels of activity and avoiding off target effects.Cogentis Therapeutics was formed at Johns Hopkins University upon winning the NIH NeuroStartup Challenge and licensing TFP5 from NINDS. Our aim is to de-risk and develop TFP5 so pharmaceutical companies will be willing to test the asset in large-scale clinical trials. TFP5, thus far, has been shown to enter the 5xFAD mouse model brain (via microscopy with fluorophore-labeled drug), engage its target, normalize tau hyperphosphorylation, reduce plaques and inflammation (proof of principle), and reverse cognitive/motor dysfunction. Although TFP5 has an extensive data package in multiple mouse models, there are several key preclinical milestones that must be achieved before a major pharmaceutical company(s) will be willing to invest in this asset to develop a product for the treatment of neurodegenerative disease. These milestones were discussed at length with representatives from multiple pharmaceutical companies and they include: 1) verification that the drug crosses the blood-brain-barrier by mass spectrometry with preliminary brain vs blood pharmacokinetic ratios, 2) Higher-resolution dosing schemes and target engagement pharmacodynamic profiles, and 3) evidence in nonhuman primates for blood brain barrier penetration/target engagement. Phase 1 of our SBIR will achieve the first 2 items, and if successful, we will apply for phase 2 to fund the third item and prepare for clinical trials.We have licensed a novel therapy from the National Institutes of Health which shows great promise for treating Alzheimer’s disease and other neurodegenerative conditions. We will perform the necessary experiments to get it ready for clinical trials. This therapy, if successful, has the potential to halt or even reverse dementia, alleviating a major strain on the global society.