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.

Regulation of CDKL5 Function by Type I Interferons"

Awardee: Josephine Thinwa, PhD

Institution: UT Southwestern Medical Center, USA

Award Amount: $150,000

Funding Period: May 1, 2025 - April 31, 2026

Development of a tau hyperphosphorylation assay in CDKL5 deficiency disorder iPSC-derived neurons

Awardee: Jedd Hubbs, PhD

Institution: Boston Children's Hospital, USA

Award Amount: $149,050

Funding Period: May 1, 2025 - April 31, 2026

Exploiting microRNAs to disclose novel pathophysiological mechanisms, biomarkers and therapeutic approaches for CDKL5 deficiency disorder

Awardee: Maurizio Giustetto, PhD

Institution: University of Torino, Italy

Award Amount: $134,300

Funding Period: May 1, 2025 - April 31, 2026

Preclinical Investigations Of Proteasome and Lysosome Inhibitors In CDKL5 Deficient Mice"

Awardee: James Eubanks, PhD

Institution: University Health Network - Krembil Research Institute, Canada

Award Amount: $147,896.00

Funding Period: May 1, 2025 - April 31, 2026

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.

Investigating clonal expansion of pathogenic T cells in idiopathic multicentric Castleman disease

Awardee: David Fajgenbaum

Institution: University of Pennsylvania

Grant Amount: $58,775

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Idiopathic multicentric Castleman disease (iMCD) is a rare and deadly hematologic illness that occurs for an unknown cause. Patients often die due to their immune system becoming hyperactivated and shutting down vital organs. The causes and key immune cell types involved in iMCD are not well understood and this limited understanding has prevented the development of better treatment strategies, resulting in poor overall survival. Our Lab has discovered that a particular cell type called the T cell appears to be highly activated and playing an important role in iMCD. The overall goals of this study are to dissect the mechanisms behind T cell activation in iMCD and determine if changes to these T cells can predict the onset of disease activity.

Targeting biomolecular condensates, as a novel approach to ameliorate SYNGAP1-related synaptopathy

Awardee: Kristian Strømgaard

Institution: University of Copenhagen

Grant Amount: $74,851

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Neurophase is a project hosted and funded by the BioInnovation Institute, a non-for-profit foundation in Denmark aiming to bridge the gap from academic research to company creation and real-life implementation of new ideas. Based on work from Professor Strømgaard from the University of Copenhagen, Neurophase has a team of talented scientists and experienced drug developers aiming to develop new drugs to help patients suffering from neurodevelopmental disorders. Neurophase is focused on diseases caused by mutations in proteins of the post-synaptic density (PSD), in particular SynGAP1 and PSD-95. The PSD is formed by formation of so-called biomolecular condensates, a novel concept of how protein complexes are formed and regulated and has recently been shown to be affected by mutations causing SYNGAP and PSD-95 associated synaptopathies. We design a new class of drugs by directly targeting the condensates of the PSD, to aid their proper formation and function. It is the goal of the project to generate data to support further investment, and within the next 24 months to establish as an independent company dedicated to treatment of neurodevelopmental disorders. Additional funding at this stage of our journey will greatly improve our ability to test our approach in multiple different disease relevant biological cell and animal models.

Mapping Molecular and Behavioral Impacts of SETBP1 Deficiency in Zebrafish

Awardee: Alexander Little

Institution: McMaster University

Grant Amount: $68,544

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

This research aims to investigate how the loss of the SETBP1 gene affects zebrafish behavior and biology, with the goal of identifying potential treatments for SETBP1 haploinsufficiency disorder (SETBP1-HD), a genetic condition that causes developmental delays and intellectual disabilities in humans. Zebrafish are a valuable model for studying human diseases and screening potential therapies. We have created two zebrafish models that replicate aspects of SETBP1-HD by knocking out the SETBP1 gene, providing a unique opportunity to study compensatory mechanisms that may mitigate the effects of the disorder. Our study will explore the behavioral and physical changes in these zebrafish, examine how SETBP1 deficiency impacts the brain and muscle tissue, and use computational analysis to screen over 500 FDA-approved drugs to identify potential therapeutic candidates. Promising drugs will then be tested to evaluate their ability to reverse the effects of SETBP1 deficiency, potentially leading to viable treatments for SETBP1-HD.

Assessing Excitation-Transcription Coupling in SCN2A-Related Disorder Mouse Models

Awardee: Jennifer Kearney

Institution: Northwestern University

Grant Amount: $62,492

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Excitation-transcription coupling is a process that facilitates learning and adaptation to new experiences/stimuli by connecting brain activity to changes in neuronal connections. Altered excitation-transcription coupling has been implicated in other neurodevelopmental disorders and may underlie disrupted sensory processing. SCN2A plays a critical role in backpropagation of action potentials, which is an important electrical signal for excitation-transcription coupling. This raises the possibility that excitation-transcription coupling may be altered in SCN2A-related disorders. Our project will investigate whether excitation-transcription coupling is affected in three SCN2A-related disorder mouse models carrying variants with loss-of-function, gain-of-function or mixed effects on channel function. First, we will examine excitation-transcription capability in isolated neurons. Next, we will evaluate excitation-transcription coupling in mice engaging in behavioral tasks that are dependent on touch. Implicating altered excitation-transcription coupling in SCN2A-related disorders would reveal a downstream point of convergence with other neurodevelopmental disorders and may suggest strategies for interventions focused on shared downstream targets.

Leveraging Human iPSC Derived Beta Cells to Investigate the Impact of Novel Therapeutics in Patients with Congenital Hyperinsulinism

Awardee: Mansa Krishnamurthy

Institution: Cincinnati Children's Hospital Medical Center

Grant Amount: $77,165

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Congenital Hyperinsulinism (CHI), the most common etiology of persistent hypoglycemia in infants and children, can be due to mutations in KATP channels, transcription factors and enzymes. Current treatment approaches include a medication called Diazoxide. Unfortunately, this medication is associated with significant side effects including fluid retention, bone marrow suppression and severe vomiting, emphasizing the need for alternative therapies with improved safety profiles. Recently, several promising candidates have emerged with the potential to suppress insulin secretion in CHI, including exendin (9-39) and compounds SW269324 and SW297577. In our lab, we can turn stem cells from patients with CHI into pancreatic beta cells, allowing us to test the effects of exendin (9-39), SW269324 and SW297577 on insulin secretion. In this proposal, we will use patient derived beta cells from ABCC8, HADH and FOXA2 to investigate the effects of exendin (9-39), SW269324 and SW297577 on insulin secretion alone and in addition to diazoxide. Through these studies, we hope to better understand the pathophysiology of CHI and develop a more personalized treatment approach for patients with CHI.

Safety, Accuracy, and Feasibility of Continuous Glucose Monitoring in Infants in the Inpatient NICU Setting with Hyperinsulinism and Hypoglycemia

Awardee: Paul Thornton

Institution: Cook Children's Medical Center

Grant Amount: $77,165

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Hyperinsulinism is a group of hypoglycemic disorders that may occur in newborns. Early detection and management are crucial as prolonged hypoglycemia can lead to neurological damage and developmental delays. Continuous glucose monitoring (CGM) offers a promising solution by providing the clinical team with a continuous trend of glucose concentration over time. This enables early detection of falling glucose levels and presents opportunities for timely intervention. Our goal is to assess the safety, accuracy, and feasibility of CGM in infants with hyperinsulinism in in-patient NICU settings. We will also use results from our study to improve data collection in the Hyperinsulinism registry by developing surveys about the use of CGM in a NICU setting and the parents’ experience and satisfaction with the CGM.

Tcf4 in gut development; investigating underlying causes of gastro-intestinal problems in patients with Pitt Hopkins syndrome

Awardee: Simone Mesman

Institution: University of Amsterdam

Grant Amount: $58,602

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Many patients with Pitt Hopkins syndrome (PTHS) experience serious gastro-intestinal (GI) problems, like severe abdominal bloating and constipation. Recently, two patients in the Netherlands unexpectedly passed away due to GI complications, underlining the need to thoroughly understand these problems in order to develop better treatment. Although these GI problems have a large influence on the quality of life of patients with PTHS and their caregivers, very little research has been done to determine the underlying causes of these problems. With the current project we aim to shed light on the possible cause(s) of the the GI problems and possible therapeutic strategies to alleviate (some of) these problems. To this end we will investigate the role of Tcf4 in gut development in patients with PTHS and in specific mouse models carrying Tcf4 mutations. To determine whether Tcf4 functions in the gut or in gut development, we will examine the normal expression pattern of Tcf4 in the human and murine gut. Next to this we will investigate the cellular and molecular architecture of the gut in patients with PTHS and mice carrying specific Tcf4 mutations. Furthermore, we will study co-morbidity of GI problems with other PTHS symptoms to determine whether specific symptoms may be related to each other. Taken together, the results from this study will help us identify the underlying causes of GI problems in patients with PTHS and pinpoint possible therapeutic targets. Furthermore, it will help us fine-tune existing treatments specifically aimed to alleviate GI problems in PTHS.