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

> **NIH NIH R43** · COGENTIS THERAPEUTICS, INC. · 2020 · $236,325

## Abstract

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.

## Key facts

- **NIH application ID:** 10023553
- **Project number:** 3R43AG062058-01S1
- **Recipient organization:** COGENTIS THERAPEUTICS, INC.
- **Principal Investigator:** Sanjeev Thohan
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $236,325
- **Award type:** 3
- **Project period:** 2018-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023553

## Citation

> US National Institutes of Health, RePORTER application 10023553, Development of CDK5-p25 modulator to treat Alzheimer's Disease and Frontotemporal Dementia (3R43AG062058-01S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10023553. Licensed CC0.

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