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: Sheba Medical Center and Tel Aviv 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.

Using human retinal organoids to discover mechanisms and therapies for CRB1 retinopathy

Awardee: Brian Ballios

Institution: University Health Network

Grant Amount: $66,991

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

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Summary:

Mutations in the CRB1 gene cause early cellular disorganization of the retina and loss of the light-sensitive photoreceptors in the eye, leading to irreversible blindness in children and adolescents. No treatments exist for these diseases. Structural differences between rodent and human retinal tissue preclude the use of animal models to uncover new therapies. Our work uses human CRB1 patient-derived stem cells to generate retinal “mini-organs in a dish” (organoids) to model CRB1 disease in the lab. Retinal organoids exhibit the same structure and major cell types found in the human retina; our CRB1 retinal organoids have the exact genetic makeup as the patient they were derived from. Comparisons of early retinal development in our CRB1 organoids with those derived from a healthy donor have shown defects in cell birth and proliferation. We aim to characterize how these early abnormalities affect the mature structure and organization of the retina in older organoids. We will analyse gene expression differences between healthy and CRB1-diseased organoids to uncover mechanisms and pathways involved in causing the disease state. These will serve as targets for testing new therapies for CRB1 disease using drugs known to modulate those pathways, and observe whether we can reverse early developmental defects.

Deciphering perturbations of primary cilia in Okur-Chung neurodevelopmental disorder

Awardee: Abdelhalim Loukil

Institution: Sanford Research Institute

Grant Amount: $60,013

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

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Summary:

The proposed project aims to investigate how mutations in the Csnk2a1 gene contribute to a rare genetic disorder called OCNDS, which causes speech difficulties, motor impairments, and cognitive issues. We will look at how these mutations affect the function of primary cilia, which are tiny hair-like structures in cells that play an important role in cell communication and brain development. By studying both mouse models and patient cells, we will identify the specific molecular changes in cilia caused by the gene mutation and their effects on brain development. This proposal will help us better understand how ciliary malfunction contributes to developmental difficulties in OCNDS. Additionally, we hope to uncover novel therapeutic targets by identifying the molecular pathways affected by the mutation. Our ultimate goal is to provide insights that could lead to potential treatments for the neurological challenges seen in OCNDS.

In Vivo, Non-Viral Base Editing To Correct AT Variants In Brain, Blood, Lung, and Liver

Awardee: Xizhen Lian

Institution: Johns Hopkins University

Grant Amount: $41,740

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

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Summary:

Ataxia telangiectasia (A-T) is a multi-organ disorder caused by recessive mutations in the ATM gene, which encodes a master regulator of the DNA damage response and impacts redox balance, angiogenesis, and glucose metabolism. In this project we will explore a base editing strategy to correct a pathogenic ATM mutation to initiate the PIs' efforts towards precision gene therapy for treating A-T. Specifically, the PIs have access to ATM patient cells harboring the R2598X mutation, and this variant is amenable to base correction. Employing lipid nanoparticles, the most clinically advanced nonviral gene delivery technology, the PIs will demonstrate in vivo base editor delivery into hematopoietic stem cells, lung and liver to potentially alleviate A-T-related morbidity and mortality. Overall, results obtained with the support of this project will set the stage for future A-T gene therapy studies including the optimization of prime editing strategies to correct ATM and expanding delivery to the central nervous system.

Investigating Excitation/Inhibition Balance in Cortical-Thalamic Circuitry in CDKL5 Deficiency Disorder Using Human-Derived Assembloids

Awardee: Francesca Puppo

Institution: University of California, San Diego

Grant Amount: $61,007

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

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Summary:

This project focuses on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental condition that causes drug-resistant epilepsy. In CDD, the balance between brain signals that excite and inhibit activity (called the excitation/inhibition or E/I balance) is disrupted, potentially leading to seizures. Cortical-thalamic projections have been implicated with the generation of seizures. However, traditional mouse models have not been able to effectively model the seizure phenotype in CDKL5 deficiency and study the complex interactions between thalamus and cortex. To address this, we will use advanced human-derived models called corticothalamic (CTh) assembloids, which combine brain-like structures (organoids) from patients with CDKL5 mutations. These models allow us to recreate the brain circuits involved in seizures and study how their development is altered. By using cutting-edge technologies such as high-density multi-electrode arrays, calcium imaging, and optogenetics, we can precisely investigate how disruptions in the E/I balance contribute to hyperexcitability in these circuits. Our research aims to identify the key mechanisms behind seizure generation in CDD, paving the way for potential therapies. This study directly supports ongoing efforts to improve CDD disease models and uncover new targets for treatment.

Epilepsy linked toTBC1D24 Loss: pH-Targeted Pharmacological and Nanotechnological Interventions

Awardee: Caterina Michetti

Institution: University of Genoa

Grant Amount: $62,937

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

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Summary:

This project aims to exploit a new preclinical mouse model (Tbc1d24-cKO) to study early-onset epilepsy caused by TBC1D24 loss. Using this model, we will test two innovative treatment strategies targeting the root causes of hyperexcitability in neurons. The first approach involves a small molecule that enhances lysosomal acidification by stimulating the v-ATPase enzyme, restoring pH balance in neuronal cells and potentially reducing neuronal hyperactivity. The second approach involves a novel nanomachine called pHIL, which is designed to selectively inhibit overactive neurons in response to pH shifts that occur during seizures. By activating a light-sensitive protein under acidic conditions, pHIL can reduce excitability without affecting healthy neurons. This research is particularly relevant to early-onset epilepsy linked to TBC1D24 pathogenic variants, a condition with no effective treatments. Our Tbc1d24-cKO mouse model allows us to test these therapies in vivo, offering a unique opportunity to explore the underlying mechanisms of epileptogenesis and to identify robust therapeutic strategies. The proposed strategies target different aspects of the pH imbalance associated with TBC1D24 loss, and testing both approaches improves the likelihood of finding an effective treatment for early-onset epilepsy.

An iPSC-based Platform for Characterization of Neuronal Circuit Dysfunction in RASopathies

Awardee: Sattar Khoshkhoo

Institution: Brigham and Women's Hospital

Grant Amount: $58,222

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

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Summary:

RASopathies are a group of genetic disorders that affect multiple body systems and are often linked to neurocognitive issues like learning disabilities, autism, and epilepsy. These conditions arise due to overactive Ras-MAPK signaling, which plays a crucial role in brain development and function. However, the specific effects of Ras-MAPK overactivation on brain circuits are not well understood. This project aims to use patient-derived stem cells to model RASopathies and investigate how abnormal signaling impacts brain cell communication. Moreover, by testing drugs that inhibit the Ras-MAPK pathway, this proposal will evaluate the feasibility of using Ras-MAPK inhibitors as a therapeutic strategy to restore normal brain activity in affected individuals. This research platform will also enable future drug discovery for rare genetic diseases that affect brain circuits.

Investigating SETBP1 pathogenic variants in lung malformation and function using human induced pluripotent stem cell-derived organoids

Awardee: Amy Wong

Institution: Toronto Hospital for Sick Children

Grant Amount: $70,000.00

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

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Summary:

Schinzel-Giedon Syndrome (SGS) is an ultra-rare, life-limiting multisystem disorder caused by mutations in the SETBP1 gene that results in abnormal accumulation of the protein. At the genetic level, SETBP1 helps regulate the expression of genes that drives developmental processes. Therefore disruption in how this protein functions can impact a wide spectrum of developmental programs leading to abnormalities including broad neurodevelopmental impairments, gastrointestinal complications and structural malformations in multiple organs, with no cure. Lung malformations and increased risk of respiratory infections is a clinical feature in some SGS patients, the mechanism of how SETBP1 impacts how the lung cells form and function is unknown. Here, we will create lung organoids (mini lungs in a dish) from stem cells harbouring SETBP1 pathogenic mutations to better understand how the protein impacts the formation of the airway cells and function of the airways including response to respiratory virus infections.