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: Alexandra 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.

Transcriptomic Signatures in Neuroendocrine Cell Hyperplasia of Infancy (NEHI)

Awardee: Sharon McGrath-Morrow

Institution: Children's Hospital of Philadelphia

Grant Amount: $83,154

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

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Summary:

Our research has the potential to significantly improve NEHI diagnosis, enhance our understanding of disease pathogenesis, and lay the groundwork for targeted therapeutic interventions.

Bronchoalveolar Lavage Fluid-Derived Organoids as Translational Models for Neuroendocrine cell hyperplasia of infancy

Awardee: James Hagood

Institution: University of North Carolina

Grant Amount: $83,154

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

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Summary:

Neuroendocrine cell hyperplasia of infancy (NEHI) causes overgrowth of specialized lung cells called neuroendocrine (NE) cells, leading to breathing problems in infants, usually starting between 6 and 8 months of age. Our project aims to create a new model to study NEHI using a less invasive method involving fluid from the lungs, called bronchoalveolar lavage fluid (BALF), which is collected during the clinical diagnosis of lung diseases. BALF can be used to create organoid “mini-lungs” which can be used to study the interaction of NE cells with other lung cell types. By studying these organoids, we hope to understand how NEHI disrupts lung function and causes low oxygen levels. Our ultimate goal is to identify and test new treatments that could improve breathing for NEHI patients.

Quantifying Movement Patterns in Children with STXBP1 Related Disorders

Awardee: Laura Prosser

Institution: Children's Hospital of Philadelphia

Grant Amount: $69,708

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

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Summary:

Individuals with STXBP1-RD often present with movement disorders with varying severity and there is a need for accurate and consistent measurements of these unique movement patterns. Wearable sensors, which are similar in size and weight to a smartwatch, have been well-tolerated in other clinical populations to measure movement disorders. Wearable sensors can also be used in many locations, such as home, school, and clinical settings, which may offer the opportunity to include participants who would be otherwise limited by the need to travel. We are seeking support from the Million Dollar Bike Ride Grant to evaluate the potential for wearable sensors to assess and distinguish the unique movement patterns observed in individuals with STXBP1-RD.

A deep screen of RNA-based therapeutics for STXBP1 syndrome

Awardee: Chaolin Zhang

Institution: The Trustees of Columbia University in the City of New York

Grant Amount: $69,708

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

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Summary:

This project, led by Chaolin Zhang at Columbia University, aims to develop a new treatment for STXBP1 syndrome, a severe genetic disorder linked to epilepsy. The research focuses on using RNA-based therapeutics, specifically antisense oligonucleotides (ASOs), to boost the production of the STXBP1 protein, which is deficient in patients with the syndrome. ASOs have already shown promise in treating other genetic disorders, such as spinal muscular atrophy. The challenge lies in identifying the most effective RNA regions to target with ASOs. Zhang’s team has developed a high-throughput screening method using a modified CRISPR/Cas13 system, which can help pinpoint these key regions in the STXBP1 gene’s untranslated regions (UTRs). By applying this method, they hope to identify RNA elements that regulate the gene’s stability and protein production. Once identified, these elements will be validated using ASOs in human cell models to confirm their ability to restore STXBP1 protein production. If successful, this research could pave the way for a targeted treatment for STXBP1 syndrome and provide a model for developing therapies for other genetic disorders.

Exploring the profile of Extracellular Vesicles (EVs) in Lesch-Nyhan Syndrome (LNS)

Awardee: Giulia Bernardini

Institution: Università degli Studi di Siena, Dipartimento di Biotecnologie, Chimica e Farmacia

Grant Amount: $57,332

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

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Summary:

Understanding Lesch-Nyhan Syndrome Through Tiny Messengers Lesch-Nyhan Syndrome (LNS) is a very rare genetic disease that mainly affects boys. It causes severe neurological problems, including involuntary movements and self-injury, as well as high levels of uric acid in the blood, which can lead to kidney stones. The current treatment can only help to lower the uric acid levels, but these cannot cope up with neurological and behavioural problems. While we know a lot about the disease, many aspects of how it affects the brain remain a mystery. Our project focuses on tiny particles called extracellular vesicles (EVs). These are small packages released by cells that carry important messages in the form of proteins, fats, and genetic material. They help cells communicate with each other, and in brain diseases, they may play a role in how the disease develops. We aim to develop new ways to study EVs in the blood of people with LNS. By doing this, we hope to: -Understand how EVs contribute to the brain and body changes in LNS. -Identify specific markers in EVs that are unique to LNS, which could help us develop better treatments. -Lay the groundwork for creating therapies that use EVs to target the disease directly. This research could not only improve the understanding of LNS but also open the door to new treatments for this challenging and neglected disease.

Deciphering the role of ephrin B2 mutation in the pathogenesis of central conducting lymphatic anomaly

Awardee: Shoshana Greenberger

Institution: Newcastle University

Grant Amount: $62,398

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

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Summary:

Summary of the project: Recently, we have identified a novel mutation in a gene Ephrin-B2 (EFNB2) that causes a change in amino acid sequence of the protein, resulting in a severe lymphatic anomaly (CCLA) in a child patient. This child shows several severe symptoms, all linked to the function of the lymphatic system. We assume that the mutation in EFNB2 causes the disease by the disruption of the structure and function of lymphatic vessels through the erratic activity of the important signal transduction pathways. We were able to isolate the lymphatic endothelial cells (LEC) from this patient. Thus we have a unique opportunity to study the effect of this mutation on both structure and function of the lymphatic vessels. Herein we propose to study a novel genetic cause of this central conducting lymphatic anomaly by: (1) characterizing the effect of EFNB2 mutation on the cellular function and signaling in patient-derived lymphatic cells, and (2) creating a zebrafish model, with mutant EFNB2 in order to decipher the effect of the mutation on lymphatic system development, creating a tool that could be used in future drug screening. We believe that this study will expand our knowledge of the role of EFNB2 in the lymphatic disease, towards our better understanding of the underlying pathogenic processes, bringing about the possibility to find a remedy for the disease.

Serum biomarkers for diagnosis and sirolimus response in lymphangioleiomyomatosis

Awardee: Elizabeth P Henske

Institution: Brigham and Women's Hospital, Harvard Medical School

Grant Amount: $73,958

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

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Summary:

Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women. Diagnosis is often difficult and sometimes requires lung biopsy, which can be associated with significant morbidity. Vascular endothelial growth factor D (VEGF-D) is increased in the blood of some women with LAM and can serve as diagnostic tool, making biopsy unnecessary. However, about one-third of women with LAM have low levels of VEGF-D. Furthermore, additional biomarkers are needed to predict and monitor the clinical response to sirolimus, the only FDA-approved treatment for LAM. In this project, we will use SomaScan, a high-throughput platform, to measure the blood levels of more than 10 000 proteins in less than a drop of blood. The SomaScan analyses will be performed before and after the start of sirolimus therapy and in matched healthy control women. We will identify biomarkers that are elevated in LAM as compared to the control population and can thus help to diagnose LAM. We will also identify biomarkers that change after sirolimus therapy and can thus be used as surrogates of treatment response. Overall, this project will use a high-throughput platform to identify novel blood biomarkers to improve the diagnose of LAM and predict the response to sirolimus treatment.

Deciphering the splicing order of COL6A1-3 pre-mRNAs to improve the prognosis and treatment of collagen VI-related muscular dystrophies

Awardee: Karine Choquet

Institution: Université de Sherbrooke

Grant Amount: $46,611

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

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Summary:

Collagen VI-related muscular dystrophies (COL6-RD) are a rare type of childhood-onset muscle disease. Symptoms include muscle weakness and breathing difficulties. There is currently no cure for COL6-RD, which are caused by spelling errors in the genes COL6A1, COL6A2 and COL6A3. These errors are also present in the COL6 premature (pre) messenger RNAs (mRNA), which must undergo a process called splicing to become the mature mRNAs that are used to produce collagen proteins. Some of the spelling errors that cause COL6-RD lead to defects in splicing. Depending on the type of splicing defect, the disease symptoms can be milder or more severe. The type of splicing defect can also determine which type of treatment could be beneficial. However, predicting the type of splicing defect can be challenging. COL6 pre-mRNAs are very long, but splicing has only been studied for one short section of a pre-mRNA at a time. Our project will use new technology that allows to read much longer sections of COL6 pre-mRNAs. We will investigate the order in which splicing happens in the COL6 pre-mRNAs, and how this influences the type of splicing defect caused by genetic spelling errors. We will also study how communication between different parts of a pre-mRNA that are located far away from one another affects the efficiency of treatments that aim to correct COL6 splicing defects. This project will improve our understanding of how splicing goes wrong in COL6-RD and could lead to improved treatment options for some of the spelling errors that cause COL6-RD.

Novel insights into cellular interaction in collagen VI muscular dystrophy

Awardee: Malte Tiburcy

Institution: University Medical Center Göttingen

Grant Amount: $46,611

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

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Summary:

Our research focusses on building healthy and diseased human muscle from pluripotent stem cells in the dish. By applying pluripotent stem cells with patient-specific mutations, we can measure the muscle function of individual patients in the lab. Collagen VI-related dystrophy is of particular interest to us because it is not a disease of muscle cells themselves. Instead, it affects the glue that connects all cells in the muscle. How the failing glue changes the cell behavior is not clear. We would like to use our models to better understand how the glue affects cellular interaction to cause muscle dysfunction. Ultimately, we aim to find new ways of preventing the muscle weakness in collagen VI dystrophy.

From mouse to human – Establishing novel biomarkers for APBD

Awardee: Felix Nitschke

Institution: University of Texas Southwestern Medical Center

Grant Amount: $56,857

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

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Summary:

APBD is caused by recessive mutations in the glycogen branching enzyme gene (GBE1), and the consequent accumulation of poorly branched cytosolic glycogen aggregates called polyglucosan bodies (PBs) in the nervous system. There are several treatment options in different stages of preclinical development. There is a critical need for robust disease biomarkers to determine disease progression and treatment efficacy in any future clinical trial in the US. We propose to evaluate a novel glycogen-related metabolite as biomarker candidates in an integrated approach using non-invasive imaging techniques and body fluid analyses from both the APBD mouse model and patients. We will deliver systematic proof of concept and quantify glycoNOE MRI signal in APBD mice and controls. Second, we will correlate the glycoNOE signal to biochemical quantification of MOG, soluble and insoluble glycogen, as well as neuroinflammatory markers including blood and CSF NfL and GFAP. Additionally, we will probe the biomarker potential of glycoNOE MRI, NfL and GFAP in blood and CSF of a small APBD patient cohort. APBD patients will be recruited for research visit to UTSW for glycoNOE MRI brain scanning and collection of CSF, blood and urine (through UTSW biobank). High fidelity assays will be used to measure NfL and GFAP for correlation to disease state.

Development of glycogen synthase inhibitors for APBD

Awardee: Wyatt Yue

Institution: Newcastle University

Grant Amount: $56,857

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

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Summary:

In APBD, the defective branching enzyme GBE1 results in malformed glycogen being synthesised by glycogen synthase GYS1 to form clogging clumps. Drug development programmes for APBD and related diseases have largely sought to deliver an artificial version of the GBE1 gene, or turn down the native GYS1 gene, to mitigate the consequences in the disease. Our vision is to develop a daily pill of GYS1 small molecule inhibitor for APBD patients as a transformative oral therapy. Thanks to previous Million Dollar Bike Ride grant funding, we set up an innovative screening method to identify small molecule ‘hits’ that act on GYS1, which is now running. Building upon this, this project will systematically work through hits identified, to validate their mode of action and optimise the molecules to have the necessary drug-like properties including brain penetration. We will achieve this taking advantage of our unique knowhow on the GYS1 protein, as well as cutting-edge computational and chemistry expertise.

Small molecule inhibition of NOTCH3 conformational alterations

Awardee: Michael Wang

Institution: University of Michigan

Grant Amount: $101,776

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

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Summary:

CADASIL is the leading inherited cause of stroke and vascular dementia and is caused by mutations in NOTCH3. Mutations in NOTCH3 result in abnormal conformations of NOTCH3 protein. We reason that drugs that reverse the abnormal conformations of NOTCH3 may be beneficial to patients. This project aims to perform a drug screen to identify chemicals that bind to mutant NOTCH3 and, by doing so, coax it into a more normal conformation. Towards this goal, we have devised a new technique which will help screen through rationally selected drug candidates. If successful, this would be a first step in drug discovery for CADASIL, currently an untreatable disease.

Understanding the role of the lipid transport protein VPS13B in Cohen syndrome pathogenesis

Awardee: Berrak Ugur

Institution: Yale University

Grant Amount: $98,828

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

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Summary:

Mutations in the VPS13B gene cause Cohen syndrome, a rare neurodevelopmental disorder characterized by developmental delays, muscle weakness, smaller head size, and progressive vision loss. VPS13B belongs to a family of proteins involved in lipid transfer between cellular membranes, a process essential for maintaining healthy cell function, particularly in the nervous system. Although VPS13B is present throughout the body and is known to be associated with the Golgi complex (a structure involved in protein and lipid transport within cells), its exact function has remained unclear. My research has shown that VPS13B primarily localizes to a specific area of the Golgi complex and plays a role in its recovery after disruption. This suggests that VPS13B’s function in lipid transfer may help maintain the structure and function of the Golgi complex. However, more research is needed to understand how these processes affect neurodevelopment and contribute to the symptoms of Cohen syndrome. The goal of the proposed research is to further investigate how VPS13B dysfunction leads to Cohen syndrome by identifying proteins that interact with VPS13B in neurons and determining key genes that work alongside VPS13B during development, potentially revealing new therapeutic targets for Cohen syndrome.