Evaluation of a therapeutic potential of disulfiram for its repositioning against encephalopathies caused by GNAO1 mutations

Awardee: Vladimir Katanaev

Institution: University of Geneva, Faculty of Medicine

Grant Amount: $100,000

Funding Period: January 1, 2026 - December 31, 2027

Summary: This project investigates disulfiram, a repositioned FDA-approved drug, for GNAO1 encephalopathies using biochemical, cellular, and animal model studies to evaluate its efficacy and safety in treating movement disorders and seizures.

DEVELOPMENT OF PHARMACOLOGICAL CHAPERONE FOR FUNCTIONAL RESCUE OF GalphaO MUTATIONS INVOLVED IN ENCEPHALOPATHY AND MOVEMENT DISORDERS.

Awardee: Patrick M. Giguère

Institution: University of Ottawa

Grant Amount: $100,000

Funding Period: September 1, 2025 - August 31, 2026

Summary: Employing machine learning, computational modeling, and biochemical assays, this study focuses on identifying small-molecule chaperones to stabilize and restore mutant Gao protein function, offering a promising disease-modifying treatment for movement disorders and epilepsy.

Pilot clinical trial to assess efficacy of Caffeine Citrate for controlling GNAO1-related dyskinetic crises

Awardee: Serena Galosi

Institution: Sapienza University, Rome

Grant Amount: $100,000

Funding Period: September 1, 2025 - August 31, 2026

Summary: A collaborative team of GNAO1 researchers, investigating caffeine citrate’s ability to control GNAO1-related dyskinetic crises, this study combines preclinical research in animal models with a phase 2 clinical trial to provide scientific evidence for caffeine citrate as a first-line treatment option.

GNAO1-related epilepsy: genotype-phenotype correlations

Awardee: Erika Axeen

Institution: University of Virginia

Grant Amount: $40,000

Funding Period: August 1, 2025 - July 31, 2026

Summary: This study leverages a clinician-validated phenotype database to improve diagnostic accuracy, identify genotype-phenotype correlations, and refine personalized therapeutic strategies for GNAO1 epilepsy patients.

Pre-clinical development of a CRISPR-mediated gene therapy for GNAO1 Encephalopathy using patient stem cells and a mouse model

Awardee: Blair Leavitt

Institution: University of British Columbia

Grant Amount: $100,000

Funding Period: August 1, 2025 - July 31, 2026

Summary: Using patient-derived stem cells and a specialized mouse model, this research aims to develop a targeted correction for the R209H mutation.  Lipid nanoparticle (LNP) technology will refine gene-editing delivery methods for clinical applications.

Development of second generation AAV gene therapy for GNAO1 deficiency

Awardee: Miguel Sena-Esteves

Institution: University of Massachusetts

Grant Amount: $100,000

Funding Period: August 1, 2025 - July 31, 2026

Summary: This study utilizes gene silencing and replacement strategies with the innovative BI-hTFR1 capsid to enable efficient brain-wide gene delivery, paving the way for future clinical trials in GNAO1 therapy.

An Evaluation of Gene Modification Strategies for Bloom Syndrome

Awardee: Caroline Kuo

Institution: University of California, Los Angeles

Awarded: $50,000

Funding Period: April 1, 2025 – March 31, 2026

Summary: To date, no studies have assessed the feasibility of gene modification as a potential treatment for Bloom syndrome. This project outlines specific aims that include proof-of-concept experiments essential for evaluating the viability of gene therapy as a therapeutic option for this condition

The Somatic Mutational Landscape Of Blm-Deficient Tumors: Finding Clues for Future Therapeutic Opportunities

Awardee: Richarda de Voer

Institution: Radboud University Medical Center (Stichting Radboud Fonds)

Awarded: $150,000

Funding Period: April 1, 2025 – March 31, 2027

Summary: Despite cancer surveillance strategies >80% of individuals with Bloom syndrome (BSyn) will have developed a malignancy by the age of 40 years. Treatment of malignancies in individuals with BS is still mostly based on standard-of-care treatments. With this proposal we aim to unravel the (mutational) mechanisms responsible for tumor initiation and progression in individuals with BSyn. We expect to gain insights into the processes relevant for tumor development in individuals with BSyn, leading to clues for future therapeutic opportunities. We will repurpose archived tumors from individuals with BSyn to:

1. Perform whole-exome or whole-genome sequencing to determine the somatic single base and small indel mutation landscape, investigate mutational signatures of defective DNA repair, mutated driver genes and identify potential signs of homologous recombination deficiency (HRD);

2. Explore the immune landscape of tumors using multiplex immunohistochemistry.

Novel Approaches to Cancer Surveillance in Bloom Syndrome

Awardee: Vivian Chang

Institution: University of California, Los Angeles

Awarded: $150,000

Funding Period: April 1, 2025 – March 31, 2027

Summary: There is a general lack of data on effective cancer surveillance in most rare cancer predisposition disorders and this remains a challenge for patients with Bloom syndrome as well. A landmark study of patients with a different rare cancer predisposition disorder known as Li-Fraumeni Syndrome caused by germline TP53 variants showed that biochemical and imaging surveillance is feasible and associated with improved long-term survival. Standard cancer surveillance approaches though have limitations, including expense and invasiveness, leading to decreased compliance. Emerging technologies that enable longitudinal “liquid biopsies” have shown significant promise to detect cancer through peripheral blood sampling. The long-term goal of this project is to establish an international collaboration with sharing of biospecimens and data across borders in order to develop, validate, and test effectiveness of novel, minimally invasive cancer surveillance methods.

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.

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.

Development of a validated and patient-specific GNAO1 model for screening and testing of therapeutics

Awardee: Harald Mikkers

Institution: Leiden University Medical Center, Netherlands

Grant Amount: $100,000

Funding Period: September 15, 2023 - September 14, 2024

Summary: This project will advance and improve a state-of-the-art personalized medicine tool for GNAO1. He will use funding from the Bow Foundation to create a validated stem cell GNAO1 model that opens the doors to various drug screening efforts. The work will investigate how GNAO1 impacts neurons and evaluate the suitability of the iPSC-based model for testing of therapeutics and drug responses

Testing mechanisms and intervention strategies in GNAO1 dystonia

Awardee: Kirill Martemyanov

Institution: University of Florida Scripps Institute for Biomedical Innovation and Technology

Grant Amount: $100,000

Funding Period: August 1, 2023 - July 31, 2024

Summary: This project will help advance scientific understanding about the mechanisms of dystonia. Many GNAO1 patients suffer from dystonia, commonly known as involuntary muscle movements. Bow Foundation funding will allow Dr. Martemyanov to use a mouse model to shine light on the impact of GNAO1 on dystonia and brain signals while also testing possible treatment strategies.

Personalized Anti-Sense Oligonucleotide Therapy in a Patient with GNAO1 Mutation

Awardee: Jennifer Friedman

Institution: University of California San Diego and Rady Children’s Hospital

Grant Amount: $100,000

Funding Period: August 1, 2034 - July 31, 2024

Summary: Dr. Friedman partnered with the n-Lorem Foundation to support the administration of an experimental antisense oligonucleotide (ASO) medicine that targets the GNAO1 gene. Funding from the Bow Foundation will help Dr. Friedman collect and evaluate the clinical observations of this cutting-edge treatment, including changes in baseline over time and data from predetermined outcome measures. This preclinical work will allow the research team to determine if ASO treatments for other GNAO1 patients are a viable approach for other patients.

Clinical trial for antisense oligonucleotide therapy in a patient with ADLD

Awardee: Margot Cousin

Institution: Mayo Clinic

Grant Amount: $50,000

Funding Period: May 1, 2023 - April 30, 2024

Summary: The long-term research goal is to advance disruptive innovation to transform care for individuals with ADLD through the development of a translational therapeutics program using team science. We hypothesize that a gapmer ASO to knockdown LMNB1 expression will be safe and well tolerated and that it will ultimately improve clinical outcomes in patients with ADLD. The objectives in this application are to develop and execute a first-in-human clinical trial to determine safety, tolerability, and potential clinical benefit of an LMNB1-targeted ASO therapy in a single patient with ADLD.

Development of 3D ADLD microfiber and organoid models for studying biomarkers and drug testing

Awardee: Stefano Ratti

Institution: University of Bologna

Grant Amount: $50,000

Funding Period: May 1, 2023 - April 30, 2024

Summary: The project aims at developing reliable ADLD microfiber and organoid models for investigating
biomarkers and for drug testing. The novel models to be developed with this substantial 1 -year funding include 3D microfiber co-cultures of astrocytes and oligodendrocyte precursors (OPCs) and brain organoids. These models will be created from the fibroblasts of patients with the LMNB1 gene duplication and deletion phenotypes and healthy donors.  

Analyzing CNS cell type specific transcriptomics in ADLD

Awardee: Quasar Padiath

Institution: University of Pittsburgh

Grant Amount: $50,000

Funding Period: May 1, 2023 - April 30, 2024

Summary: In this proposal, ADLD brain tissue samples will be utilized to carry out both bulk and
CNS cell type specific transcriptomics (RNA Seq analysis). Such an analysis will identify pathways there are perturbed as a result of lamin B1 overexpression and interrogate lamin B1 overexpression across different CNS cell types. These studies will help identify pathways contributing to the demyelination phenotype that may serve as potential therapeutic targets. In addition, cell type specific analysis can identify cells that are targeted for lamin B1 overexpression and cell type specific pathways that are perturbed providing critical insights into which cell types are responsible for the disease process.