2025 CDKL5 Program of Excellence Pilot Grant Program - Full Application

The ODC and Loulou Foundation CDKL5 Pilot Grant Program provides a one‐year grant for $150,000.00 (total cost) to support research related to CDKL5 Deficiency Disorder (CDD). The number of awards is not fixed and may vary.

Background

CDKL5 Deficiency Disorder (CDD) is a monogenic, neurodevelopmental disorder characterized by treatment-resistant epilepsy and severe neurodevelopmental delay. The disease is caused by loss-of-function mutations in a protein kinase called CDKL5 which is responsible for normal neuronal function. The mechanisms by which loss of CDKL5 expression leads to this neurodevelopmental disorder remain unclear. The gene encoding this protein is located on the X chromosome, with heterozygous females primarily affected. The disease does not exhibit neurodegeneration, and animal models strongly suggest the potential for reversibility of phenotypes associated with loss of CDKL5. While clinical development of novel therapeutics is underway, the current standard of care is not fully effective at managing seizures in all patients, or in the treatment of non-seizure symptoms such as neurodevelopmental or motor deficits.

We are seeking grant applications that progress the discovery or development of treatments and/or cures for CDKL5 Deficiency Disorder. Because many gaps still remain in our understanding of the biology of CDKL5 and its role in neurological development and function, applications that address such gaps in basic science are welcome, provided that they are tethered to the development of a potential therapy. While the RFA is broad in scope, priority will be given to grants that cover the following areas:          

1) Novel therapeutic approaches for CDD, including, but not limited to, techniques in genome editing, RNA-based mechanisms, biologics, novel cell-based therapeutics, network modulation, and development of novel therapeutic compounds, including through small molecule repurposing or screening against validated phenotypes in human cellular systems. Also encouraged are novel delivery systems for gene therapy and genome editing cargoes.        

2) Establishment of the link between molecular function of CDKL5 and disease pathophysiology in cellular or animal disease models through rescue or modulation of molecular, cellular, or behavioral deficits via pharmacological or genetic / gene therapy interventions.

• Projects are considered that will expand our understanding of the genomics, biochemistry, and cell biology of the CDKL5 gene, mRNA, and protein kinase, including upstream regulation of the gene or protein; and broader understanding of downstream kinase targets, as contributors to pathology and/or possible therapeutic interventions.
• Phenotypic reversal in rodent models should include the use of adult (e.g., 4 months of age or older) animals, to address effects over the natural history of the phenotype in the animal model. 
• Proposals are also encouraged to study phenotypic reversal in newly emerging biological domains, such as primary cilia function and microtubule dynamics, and peripheral organ systems, as well as potential novel functions of CDKL5 in distinct subcellular compartments (e.g., nucleus, post-synaptic density; nucleic acid binding), provided that a link to pathophysiology can be established or hypothesized.

3) Systems biology and computational modeling approaches to provide a deeper understanding of CDKL5 function, downstream effectors, intracellular signaling, protein:protein interactor networks, or genetic modifiers from model organisms and human cellular models, including regulators of CDKL5 gene expression, or the expression of CDKL family members.

4) Discovery and validation of CDKL5 biomarkers (molecular and functional) and clinical outcome development with the goal of translation to the clinical setting.

1. Molecular biomarker discovery and validation of candidate biomarkers in patient and model system fluids such as plasma and CSF.
2. Novel application of imaging and functional techniques to characterize the disease state of CDD pre-clinical models or in the clinical setting. A non-exclusive list of topics that would be responsive to this RFA is listed below:

• Functional/structural MRI; magnetic resonance spectroscopy (MRS); diffusion tensor imaging (DTI).
• EEG and stimulus-induced event-related potentials.
• Proposals are encouraged which would address potential reversal of these imaging and functional deficits by CDKL5 genetic / gene therapy or pharmacological interventions in CDD disease models, and potential mechanisms of CDKL5 function in these systems.
• Clinical outcome development for CDD, including in domains such as visual function, fine motor/hand use skills, etc.

 Eligibility 

All individuals holding a faculty‐level appointment at an academic institution or a senior scientific position at a non-profit institution or foundation are eligible to respond to this RFA. Biopharmaceutical companies are not eligible to apply; however, we will consider applications from for-profit organizations that provide services responsive to the RFA, as collaborators with a qualified academic faculty-level staff member.       

Full Application Form Due Date: 

Document is to be uploaded no later than 5pm (EST) on Friday, March 21, 2025. 

Please review the RFA Guidelines before submitting your full application.  

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