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Cure CASK Gene Therapy Research Program

Cure cask

The Theory

The goal of the UC Davis research program is to develop and test a new therapeutic approach that could be transformative for girls living with CASK.

This research is based on a key biological principle. Females have two X chromosomes, and the CASK gene is located on the X chromosome. In almost every cell of a female’s body, however, only one of these X chromosomes is active, while the other is naturally switched off through a process known as X-chromosome inactivation.

 This project aims to “switch on” that silenced healthy copy so it can produce CASK protein. Importantly, because this strategy seeks to restore the body’s own natural gene expression (rather than add extra copies of the gene), it is designed to aim for normalisation of CASK levels, not overexpression.

In theory, increasing CASK protein levels in the brain could meaningfully improve neurological function and, as a result, improve outcomes for those affected.

The Research Program

To keep the work rigorous and to move forward as funding becomes available the program has been structured in phases.

Phase 1

Funded and underway – CASK Coalition Award of $140,000

Objective: Create human induced pluripotent stem cells (iPSCs), grow them in a dish, and differentiate them into relevant brain cell types to evaluate the feasibility, efficacy, and efficiency of CASK reactivation.

Status:

Phase 1 of this research has delivered an important breakthrough in our understanding of CASK and its therapeutic potential. Supported by funding from the CASK Coalition, researchers in the Fink and Halmai labs at UC Davis have shown that reactivating CASK in human brain cells is possible. This is a significant advance because it suggests that future therapies may be able to restore the function of the healthy copy of the CASK gene and address the underlying cause of CASK disorders. Please click here to learn more.

Timing: This phase commenced in about 1 February 2024 and completed in about March 2026.

Phase 2

Objective: Characterise mouse models of cask, assess whether the therapeutic approach can reactivate the healthy copy of cask in the brain, and evaluate the degree of functional recovery that may be achievable.

This phase is structured into 5 components.

Task 2.1 – Building Mouse Colony 

Task 2.2 – Behavioural phenotyping 

Task 2.3 – EEG and identification of neurophysiological phenotypes 

Task 2.4 – Bridging mouse and human data (connecting Aim 1 and Aim 2) 

Task 2.5 – Human-to-mouse bridging for functional efficacy 

Status: Cure CASK USA Award of $70,945 Building of Mouse Colony 

Professor Jill Silverman’s team received CASK mice from Jax Labs and began establishing a colony in June 2025. This has been progressing well. To keep updated as to the progress please follow us @curecaskusa

FUNDRAISING GOAL $105,000 HELP US FUND THE NEXT STAGE OF PHASE 2

Cure CASK USA is now fundraising to support Tasks 2.2, 2.3 and 2.4 of Phase 2, with all funds received contributing directly to this critical research program.

Following the successful establishment of the mouse colony, the next phase of research will focus on:

  • Behavioural phenotyping
  • EEG and identification of neurophysiological phenotypes
  • Bridging mouse and human data

These next steps are essential to helping researchers better understand how CASK affects the brain and behaviour, while identifying measurable markers that can be used to test future therapies.

As this work has progressed, it has become clear that observing behaviour alone is not enough. Seizure and sleep-related behaviours are far more meaningful when paired with EEG recordings of brain activity. This allows researchers to see, in parallel, what the animal is doing and what the brain is doing, giving a much stronger and more complete understanding of CASK-related function.

Importantly, this work also helps bridge what is seen in mouse models with what may be relevant in humans. By connecting behavioural and brain-based findings, the team can identify more reliable phenotypes and move closer to understanding whether reactivation of the healthy copy of CASK in the brain may lead to meaningful functional improvement.

Every donation received will directly support this next stage of Phase 2 and help bring us closer to better understanding, better measurement, and ultimately move close to a future treatment for females with CASK.

 

Background and Rationale

This research builds on advances in other X-linked neurodevelopmental conditions, including Rett syndrome and CDKL5 deficiency disorder, where X-reactivation approaches have shown proof-of-concept success in mouse models.

UC Davis is seeking to apply and test similar techniques with the CASK gene, a gene that displays markers consistent with being a strong candidate for this novel therapeutic strategy.

UC Davis California 

The UC Davis MIND Institute located in California is a collaborative international research center, committed to the awareness, understanding, prevention, and treatment of the challenges associated with neurodevelopmental disabilities and rare x linked disorders.

Kyle Fink

Assistant Professor University of California Davis, Department of Neurology
Therapeutic Research Project
Fundamental Biology
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Lavvina Thiyagarajan

MBBS

Lavvina is a clinical genetics fellow from NSW, Australia with a background in general paediatrics. She has practiced in multiple tertiary paediatric hospitals in Australia, both in general paediatrics and clinical genetics. She currently provides specialist advice for the NGO, Taking Paediatrics Abroad and is a member of GeneEQUAL, an inclusive research group aiming to improve accessibility of genetic testing and care for people with intellectual disability by co-design.

Lavvina’s clinical interests are in the genetics of autism, intellectual disability and immunogenomics. She is particularly passionate about including the patient groups she works with in research and healthcare decisions.

Lavvina is affiliated with The Children’s Hospital Westmead and the University of New South Wales where she is undertaking a Masters by Research, co-producing a model of genetic healthcare that aligns with the preferences of Autistic people.

Permission to Use Photos and Media

I, the undersigned, give my consent to the Angelina CASK Neurological Research Foundation Ltd and Angelina CASK Neurological Research Foundation Inc (ACNRF) to use photographs, videos, or other media featuring me, my child, or an individual under my legal guardianship (“Media Materials”).

This consent permits ACNRF to use these Media Materials for purposes such as:

  • Raising awareness of CASK-related disorders
  • Promoting ACNRF’s initiatives, campaigns, and programs
  • Sharing on ACNRF’s website, social media, newsletters, and other communication channels
  • Use in advertising, educational resources, and fundraising efforts.

I understand that these materials may be distributed publicly and may appear in print, digital, and other media formats worldwide and in perpetuity.

Terms and Conditions:

1. Usage Rights: I grant ACNRF the right to edit, adapt, or modify the Media Materials as needed for the purposes outlined above.

2. No Compensation: I acknowledge that no monetary or other compensation will be provided for the use of the Media Materials.

3. Release of Claims: I waive any rights to inspect or approve the final product and release ACNRF from any claims, liabilities, or damages related to the use of the Media Materials, including but not limited to claims of defamation, privacy, or copyright infringement.

4. Ownership Confirmation: I confirm that I have the authority to grant these rights for the provided Media Materials and that they do not infringe on the rights of any third party.

This authorisation is voluntary and may be revoked by written notice to ACNRF at any time, though I understand that materials already published may not be withdrawn.

“In some ways, that CASK-linked pathology is degenerative in nature provides a positive outlook. Because microcephaly in CASK-linked pathology progresses postnatally, there may be a temporal window when therapeutic intervention might prevent or slow further brain cell loss. Regression, even in adolescence, has also been observed in some cases of MICPCH [119], again offering the tantalizing possibility that a therapeutic approach might prevent such decline under conditions when degeneration is known to progress. The potential benefits of intervention might extend even further given that non-cell-autonomous toxicity could also affect functioning of the remaining neurons; reduction of such toxicity, especially when coupled with high-intensity rehabilitative measures [120], might offer real hope for a positive impact on functional outcomes.”   

https://www.mdpi.com/2073-4409/11/7/1131/htm