Translational research for CASK-related disorders

Awardee: Dr. Mingshan Xue

Institution: Baylor College of Medicine

Grant Amount: $375,000

Summary: There is an urgent need to develop new therapeutics that can broadly and effectively improve neurological function in people with CASK-related disorders, both female and male. The objective of Dr. Xue’s research is to develop robust mouse models and genetic therapies for CASK-related disorders. The funding from Project CASK will support the early phase of this translational research program, with the ultimate goal of moving toward proof of concept for a gene replacement therapy for CASK-related disorders. This funding is to support (i) the development and characterization of at least one neurobehavior model and (ii) the optimization of the gene therapy approach and initial testing on epilepsy phenotypes, with the understanding that both male and female models will be supported through this funding.

The role of the CASK/Liprin-α interaction in pontocerebellar hypoplasia: a translational approach

Awardee: Drs. Hans-Juergen Kreienkamp and ChangHui Pak

Institution: University Medical Center Hamburg-Eppendorf

Grant Amount: $250,000

Summary: This project will map phosphorylation sites in Liprin-alpha variants, and identify which sites contribute to LLPS in a human cell line, and synapse formation in cultured neurons. They will test whether the SAD-inhibitor GW296115 can replace CASK in this pathway. Furthermore, they will generate human iPSC models bearing CASK missense variants from patients with a severe phenotypic outcome (EllSK, R25SC), as well as a CASK deficient model; adopt in vitro differentiation to generate human cerebellar organoids, Purkinje and granular cells; and analyse these for synapse formation and connectivity, but also eventual pathological signs of neurodegeneration and cell death.

Profiling CDKL5 signaling landscape at the synapses

Awardee: W. Andy Tao

Institution: Purdue University

Award Amount: $150,000

Funding Period: May 1, 2024 - April 31, 2025

CDKL5 in Biomolecular Condensates and its Role in CDD Pathophysiology

Awardee: Keren Lasker

Institution: The Scripps Research Institute

Award Amount: $150,000

Funding Period: May 1, 2024 - April 31, 2025

Cortical Visual Impairment in CDKL5 Deficiency: Dissecting the Link between Functional Deficits and Molecular Mechanisms

Awardee: Jacque Pak Kan Ip

Institution: The Chinese University of Hong Kong

Award Amount: $150,000

Funding Period: May 1, 2024 - April 31, 2025

Looking for differences: in vitro isolation of hCDKL5-specific antibody fragments and set-up of a method to quantify hCDKL5 and possibly distinguish between its isoforms.

Awardee: Ario de Marco

Institution: University of Nova Gorica

Award Amount: $150,000

Funding Period: May 1, 2024 - April 31, 2025

Integrating Experimental and Computational Approaches to Unravel the Neurophysiological Basis of CDKL5 Deficiency Disorder

Awardee: Roy Ben-Shalom

Institution: UC Davis

Award Amount: $148,442

Funding Period: May 1, 2024 - April 31, 2025

Genetic models to progress treatments for IQSEC2 related pharmacoresistant epilepsy.

Awardee: Cheryl Shoubridge

Institution: University of Adelaide

Grant Amount: $30,000

Funding Period: March 1, 2024 - February 28, 2025

Summary: This project aims to generate patient derived iPS cells modelling the loss of IQSEC2 to comprehensively evaluate anti-epileptic drugs in reducing seizure activity in a human relevant setting.

Establishment of a female model of IQSEC2-associated disorders and AAV-mediatedtreatment of the phenotypes.

Awardee: Takuma Mori

Institution: Shinshu University School of Medicine

Grant Amount: $15,000

Funding Period: March 1, 2024 - February 28, 2025

Summary: This proposal aims to establish a standard strategy to understand female-specific phenotypes of IQSEC2-associated disorder using rodent models. The objectives of this project are to first produce a humanized mouse with IQSEC2-associated disorders and to investigate the physiological properties of a single neuron. The other aim of this proposal is to examine the possibility of the AAV-mediated treatment of IQSEC2-associated disorder.

A Novel Approach for the Treatment of IQSEC2-mediated Disease.

Awardee: Sahar Isa Da’a

Institution: Sidra Medicine, Qatar Cardiovascular Research Center

Grant Amount: $20,000

Funding Period: March 1, 2024 - February 28, 2025

Summary: Our proposal is centered on implementing a precise and personalized medicine approach to evaluate AMPA receptor modulators tailored for therapy specific to IQSEC2 genetic variants. Employing the zebrafish model, we aim to decipher the molecular and cellular mechanisms influenced by IQSEC2 genetic variants and their impact on neurodevelopment and phenocopying the clinical presentations of patients. The established zebrafish models will serve as a valuable tool for testing potential therapeutic drugs, specifically AMPA receptor modulators, designed for the treatment of IQSEC2-related disorders. The range of AMPA modulators includes Perampanel, known for inhibiting recycling; Ritalin and Aniracetam, recognized for increasing recycling; and PAM (PF-4778574), designed to boost AMPAR activity.