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.