Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
Keywords
Last Name
Institution

Contact Us
If you have any questions or feedback please contact us.

Pilot studies to characterize CDKL5 inhibitors


Collapse Biography 

Collapse Overview 
Collapse abstract
Pathological mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD, OMIM 300203, 300672), a relatively common genetic cause of early-life epilepsy. Recent analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. In other words, loss of kinase function seems equivalent to loss of the protein. Big gaps are present in rodent models of CDD. A key feature is missing in these models: severe epilepsy. Specific inhibitors of CDKL5 are essential for addressing the role of CDKL5 without confounding chronic effects of genetic CDKL5 deletion. A key waypoint in the path to address this question is knowledge of specific CDKL5 substrates. Our collaborator, Dr. Sila Ultanir, has determined that microtubule end-binding protein 2 (EB2) is a specific CDKL5 substrate and has developed a phoshospecific antibody. With this tool in hand, our immediate goal in this pilot project is to use this read-out of CDKL5 activity to identify sensitive and specific CDKL5 inhibitors in brain tissues. Our collaborators, Dr. Axtman and Ms. Wells, have identified additional compounds. We will use these inhibitors to address our hypothesis that the acute blockade of CDKL5 activity has unique effects on hippocampal signaling and function compared to chronic knock-out through 2 aims: 1) Identify sensitive and specific inhibitors of CDKL5 and 2) Determine effect of acute inhibition of CDKL5 on hippocampal synaptic function and plasticity. Two developmental time points will be studied. Overall Impact: Our goal in this pilot project is to identify a CDKL5 inhibitor. This will allow us to bypass the gaps in rodent models of human CDD. In future studies, we hypothesize that specific CDKL5 kinase inhibitors will be necessary to fully probe and understand CDKL5 neuronal function throughout development. Since CDD is a strong candidate for gene therapy, an important clinical question is whether gene replacement of CDKL5 later in life improves symptoms. Our future experiments are necessary to determine whether such therapy may have an optimal developmental therapeutic window. Further, it may reveal that some symptoms of CDD do not depend on CDKL5 function later in life, as these were triggered developmentally, and will require alternative interventions beyond gene replacement.
Collapse sponsor award id
R21NS112770

Collapse Time 
Collapse start date
2020-04-01
Collapse end date
2021-09-30

Copyright © 2024 The Regents of the University of Colorado, a body corporate. All rights reserved. (Harvard PROFILES RNS software version: 2.11.1)