Join IFCR Now!

IFCR Store

Partner Login

User Name:    Password: 

Glyn's Gift

The beginnings of CDKL5
Our Next Event

Natural History Study

Learn More
News

iPS Disease Modeling and Drug Development in CDKL5

Dr. Muotri will attend the IFCR Science Symposium to be held in the Chicago, IL, area in June. He has ... Learn More

GoodSearch: You Search...We Give!

Research Grants and Updates

CURRENT CDKL5 RESEARCH Funded by IFCR

 
Modeling CDKL5 Related Disorders in Mice

Zhaolan Zhou, PhD     University of Pennsylvania    2014

“Modeling CDKL5 Related Disorders in Mice”

The development of mice with CDKL5 is essential to clinically study the effects that various drugs would have in order to move research into clinical trials. Dr. Zhou's lab has created several different types of mice with CDKL5 mutations which allows us to study the molecular mechanisms that are important in the disorder and to evaluate how different types of mutations cause different types of effects.  These models have started to identify specific molecular pathways involved in CDKL5.  This project includes the creation of a reversible mouse model.  Utilizing these models, Dr. Zhou has started several trials with compounds that may help alleviate some of symptoms of CDKL5.  

Modeling CDKL5 Syndrome Using iPSC-Derived Human Neurons

Alysson Muotri, PhD     University of California San Diego    2014

“Modeling CDKL5 Syndrome Using iPSC-Derived Human Neurons”

Utilizing advanced technology this lab has successfully been able to grow neurons directly from several children with CDKL5 from s simple skin biopsy. These CDKL5 neurons allows for many areas of investigation such as looking at pathways involved in CDKL5 disorder, including some of the pathways that may cause seizures. Using single cell gene expression profiling it has been discovered that CDKL5 neurons express a unique set of neurotransmitters. It has also been discovered that there is a unique change that happens after cells are stimulated. This information allows this technology to be used to identify how different drugs affect the function and growth of the neurons, and this will lead to the discovery of various medications that can help change the outcome of CDKL5.  Also the cells will be specially screened to evaluate a specific molecular profile of CDKL5 cells, which in turn will help to determine other pathways involved with CDKL5 and could lead to more therapeutic targets.

Drug Therapy Targeted to Core Molecules in Neural Plasticity Cascades: A Promising Tool for the CDKL5 Variant of Rett Syndrome

Claudia Fuchs, PhD         University of Bologna, Italy    2014

“Drug Therapy Targeted to Core Molecules in Neural Plasticity Cascades: A Promising Tool for the CDKL5 Variant of Rett Syndrome” 

(Co-Funded with Rettsyndrome.org)

CDKL5 plays a role in a neurologic function called “plasticity” which is important for the multiple aspects of learning and memory. There are many different mechanisms that play a role in plasticity and this lab has identified some of the key pathways that involve CDKL5. Current studies include exploring existing drugs which may allow restoration of plasticity in CDKL5. If these studies show promise this would allow for a fairly rapid transition to a clinical trial. 

CDKL5 Database Registry

Dr. Helen Leonard and Dr. Jenny Downs      Telethon Kids Institute, Perth, Australia

CDKL5 Database Registry  Ongoing support

An extremely important aspect of CDKL5 research is to gain an understanding of the effects and changes that happen over time- often referred to as the "Natural History" of the disorder. This group has been studying the epidemiology of neurological disorders for many years, including Rett Syndrome and Down Syndrome. Utilizing a questionnaire developed specifically for CDKL5 we are learning so much about the spectrum of the disorder and identifying patterns of treatments and interventions that may lead to an improved quality of life for our children.   Dr. Leonard and Dr. Jenny Downs work in collaboration with the CDKL5 centers of Excellence and many families and clinicians around the world.   Please visit http://www.cdkl5.com/Research/Database.aspx to participate.

Neurochemical and Therapeutic Studies in Mouse Models of CDKL5 Disorder

Wenlin Liao, PhD       Institute of Neuroscience, National Cheng-Chi University, Taiwan   2015

“Neurochemical and Therapeutic Studies in Mouse Models of CDKL5 Disorder”

Mice with CDKL5 show impaired social communication and enhanced stereotypy which are key features of autism. These mice also develop increased impulsivity and locomotor activity, simulating features of Attention Deficit Hyperactivity Disorder (ADHD). This lab is examining how CDKL5 is causing these disorders and they have some very interesting results showing new pathways in which CDKL5 is involved. Utilizing these discoveries they will be studying therapies that may help to alleviate these problems.

Identification of CDKL5 direct substrates based on kinase linked phosphoproteomics

Weiguo Andy Tao, PhD               Purdue University   2015

“Identification of CDKL5 direct substrates based on kinase linked phosphoproteomics”

CDKL5 is a serine/threonine kinase but the complete characterization of its targets are lacking. Further identification of protein targets for this kinase is necessary in order to provide more detailed biologic effects of CDKL5.  This project is using kinase linked phosphoproteomics to further identify the phosphorylation targets of CDKL5.  

Investigation of the role of CDKL5 expression, localization and function in seizures and intellectual disability

Heather Caballes, PhD and Tim Benke, MD, PhD      University of Colorado Denver   2015

"Investigation of the role of CDKL5 expression, localization and function in seizures and intellectual disability"

CDKL5 plays roles in plasticity and development, and its disruption leads to syndromes characterized by seizures and intellectual disability; however, the exact mechanisms that lead to the development of epilepsy and intellectual disability are unknown.  The experiments proposed here will begin to elucidate these mechanisms by characterizing expression of CDKL5 in human epileptic tissue and in a rat model of early life seizures, as well as examine CDKL5 role in AMPA receptor desensitization using CDKL5 KO mice

Phenotyping of a CDKL5 Mouse Model

Pyschogenics, Inc.    New York

Phenotyping of a CDKL5 Mouse Model

The goal of the study is to assess the phenotype of a mouse models of CDKL5 with the longer-term goal of setting up a drug screen battery.

Uncovering synaptic deficits of the cerebral cortex underlying CDKL5 Disorder: The AKT/mTOR pathway as a therapeutic target”

Maurizio Giustetto, PhD  University of Turin and National Institute of Neuroscience

and

Tommaso Pizzorusso, PhD     CNR

“Uncovering synaptic deficits of the cerebral cortex underlying CDKL5 Disorder: The  AKT/mTOR pathway as a therapeutic target”

 

(starting November 2015)

 

This project will further explore CDKL5 roles in synaptic function and plasticity concentrating on therapeutic potentials with agents that can enhance this pathway and specifically drugs to increase activity of the AKT/mTOR pathway.  This project will utilize use of the mouse models and will also include the evaluation of new antibody formation.

Boston Children's Hospital Center of Excellence
Researchers: Walter Kaufmann, MD and Heather Olson, MD

Expected start date: Fall 2013
Cleveland Clinic CDKL5 Center of Excellence
Researchers: Dr. Sumit Parikh, MD

Expected start date: August 2014
Children's Hospital Colorado CDKL5 Center of Excellence
Researcher: Tim Benke, MD, Ph.D

Started: April 2013
"Investigation of the importance of an uncharacterized MeCP2 phospho-isoform for neuronal morphogenesis and chromatin related functions, and the relationship between CDKL5 and MeCP2"
Researcher: Charlotte Kilstrup-Nielsen, PhD

Laboratory: University of Insubria, Italy

Started: January 2013
"Modeling CDKL5 Syndrome using human Neurons"
Researchers: Alysson Muotri, Ph.D and Priscilla Negraes, Ph.D

Laboratory: University of California San Diego

Started: September 2012 Project: IFCR has funded an 2-year postdoctoral position for "modeling CDKL5 syndrome using human neurons". The goal is to examine specific neuronal gene expression profiles, with the aim to accelerate the discovery of novel therapeutic drugs to treat CDKL5.
Identification of CDKL5's Phosphorylation Targets
Researcher: Sila Konur Ultanir, Ph.D

Laboratories: University of California San Francisco; National Institute for Medical Research, London UK

Started: September 2012

Project: Dr. Ultanir is using a recently developed kinase substrate identification method to reveal the phosphorylation sites of CDKL5. The goal is to gain valuable information and a better understanding of the synaptic and molecular functions of CDKL5.
Development of Antibodies Against CDKL5
Researcher: Zhaolan Zhou, Ph.D

Laboratory: University of Pennsylvania Scool of Medicine, Philadelphia, PA

Started: June 2012
Australian Pediatric Surveillance Study and International CDKL5 Database Registry
Researchers: Stephanie Fehr and Dr. Helen Leonard

Institution: Telethon Institute for Child Health Research, University of western Australia

Started: June 2012

Project: As part of the Natural History of CDKL5 disorder, the Australian pediatric surveillance study will help determine the incidence and prevalence CDKL5 in Australia, thereby highlighting the impact CDKL5 disorder has on families, caregivers and society.
CDKL5 Mouse Model (Knock-In)

Researcher: Zhaolan (Joe) Zhou, Ph.D., Asst. Professor Department of Genetics

Laboratory: University of Pennsylvania School of Medicine, Philadelphia, PA

Started: July 2011, expected completion in 2013

Project: IFCR has funded a knock-in mouse model with Dr. Zhaolan (Joe) Zhou at the University of Pennsylvania. He is developing a germline transmitted knock-in mouse which will have a nonsense mutation R59X. It is imperative that different types of mutated mice are developed to be able to further develop studies to determine what the CDKL5 protein really does and to see how new drugs affect different types of mutations. This particular nonsense mutation was selected for a few reasons. It appears to be a more common mutation for CDKL5 with 5 reported cases in the literature, it is at a strategic site in the gene and we have correlative samples from both a male and female affected with CDKL5 in which iPS cells are also being developed.

Biotech companies are working to develop read-through compounds which will allow the production of RNA and protein despite having a nonsense mutation. Many of the CDKL5 affected children have this type of mutation. These studies will help to correlate activities in mouse and human cells and will help identify a reproducible cellular phenotype that would allow us to test the read-through compounds that are already available. With these correlations it will be much easier to take these compounds into clinical trials.

In Progress:

  • Continued breeding
  • Phenotype characterization (Anticipate 2013)
  • Attempt to reverse the phenotype (symptoms of CDKL5) in mice with currently available “read-through” drugs.
  • Need 2-3 other mice created with different “human” mutations to allow better phenotype characterization and allow for best model prediction of drug discovery and modifier genes
  • Correlation of mouse neuronal development with iPS neuronal development
Development of iPS cells and Differentiation into Neurons
Researcher: Alysson Muotri, PhD
Laboratory: University of California San Diego
Started: April 2011

Project: Create induded pluripotent stem cells from skin fibroblasts of patients with CDKL5 and differentiate into neuronal cells.

Update (May 2013): Multiple iPS cell lines have been successfully created and differentiated into CDKL5 neurons from males with CDKL5, and their corresponding controls. In addition, we have one cell line from a female with a nonsense mutation R59X, and one from a male with the same mutation.

In Progress:
  • Characterization of cell lines
  • Correlation to mouse lines
  • Drug screening and molecular profiling Future Studies

Required: May need more females Need to develop lines with variety of mutations
CDKL5 Mouse Model (Knock out)
Researchers: Cornelius Gross, PhD and Elena Amendola, PhD- post doctoral fellow

Laboratory: European Molecular Biology Laboratory, Monterotondo, Italy

Started: September 2010, completed 2012

Project: Create CDKL5 Knockout mouse model (Generate a mouse that lacks the Cdkl5 gene). Other labs have said that CDKL5 KO mice were embryonic lethal so this lab is using a specialized Cr:e-lox technique to create mice derived entirely from the knockout ES cells, while in the traditional procedure only part of the offspring are derived form the knockout ES cells.

In Progress:
  • Continued breeding
  • Phenotype characterization
CDKL5 Antibody Development
Researchers: Cornelius Gross, PhD and Elena Amendola, PhD- post doctoral fellow

Laboratory: European Molecular Biology Laboratory, Monterotondo, Italy

Started: September 2010, completed 2012

Project: Create 2 different antibodies against the CDKL5 protein to be used for future studies utilizing Immunflourescence for Enzyme Linked ImmunoSorbent Assays (ELISA)
Determination of CDKL5 Function
Researchers/Laboratories:
Elena Amendola, PhD- EMBL, Monterotondo, Italy
Alysson Muotri, PhD , University of California, San Diego

Project: Variety of approaches using mice, iPS, and cell cultures to determine CDKL5 function

In- Progress: Correlations between mouse and iPS

Additional CDKL5 Projects

 
iPS Cell Lines

Researchers and Laboratories:

Alessandra Renieri, MD-PhD, University of Siena, Siena Italy
John Christodoulou, MD PhD, Childrens Hospital of Westmead, Australia


Project:  Create induded pluripotent stem cells from skin fibroblasts of patients with CDKL5 and differentiate into neuronal cells.

Future Studies

  • Growth and differentiation
  • Characterization
  • Need to develop lines with a variety of mutations
  • Mouse correlates (see above)
  • Use for drug screening and molecular profiling
Determination of CDKL5 Function

Researchers/Laboratories:

  • Nicoletta Landsberger, PhD, Univ of Insurbia, Busto Arsizio, Italy
  • Bruria Ben-Zeev, MD, Sheba Medical Center, Israel
  • Thierry Bienvenu, MD Institut Cochin, Universite´ Paris Descartes, CNRS (UMR 8104), Paris, France
  • Elisabetta Ciani, Ph.D, University of Bologna, Italy
  • Alessandra Renieri, MD-PhD, University of Siena, Siena Italy
  • John Christodoulou , MD PhD, Childrens Hospital of Westmead, Australia 
  • Zhiqi Xiong, PhD, Institute of Neurosciences in Shanghai, People's Republic of China

 

All in progress

© 2017