2025 BDGRI Grant Recipients
Defining the anatomical basis of dysphagia or the inability to swallow in Batten disease
| CHIEF INVESTIGATORS: | Professor Jonathan Cooper, PhD and Ewa Ziółkowska, PhD |
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| AFFILIATION: | Washington University in St Louis, MO. USA |
| AMOUNT: | USD $50,000 |
Cooper
Jonathan Cooper is a neuroscientist who leads the Pediatric Storage Disorders Laboratory (PSDL). This is based at Washington University in St Louis, where Dr. Cooper is a Professor of Pediatrics, Genetics, and Neurology. His lab works to understand how different forms of Batten disease affect the brain and to devise and test experimental therapies to treat these effects. Inspired by conversations with Batten families, he has been increasingly studying the impacts of disease outside the brain. This includes effects upon the bowel, peripheral nervous system, and muscles, all of which appear treatable via gene therapy in Batten mice. This project will explore the basis of swallowing problems or dysphagia across multiple forms of Batten disease. These symptoms represent a serious and life-threatening feature of Batten disease, but very little is known about their cause.
Ziółkowska
Ewa Ziółkowska, is a postdoctoral research associate in Dr. Cooper’s Pediatric Storage Disorders Laboratory (PSDL). She joined the PSDL in 2023, after completing her PhD studies on the bowel and muscles, and other organs in her native Poland. She has been a crucial part of the lab’s recent work on studying the effects of Batten disease upon these parts of the body, testing the effects of gene therapy upon them. She devised this project on swallowing problems after discussing their distressing impact upon affected families. This project combines her new expertise in brain analysis, learned in Dr. Cooper’s lab, with analysis of nerves and muscles involved in swallowing, and the esophagus. We are also working with collaborators to image swallowing in our mice. These studies will pave the way to testing whether gene therapy can treat these underappreciated but deadly symptoms of Batten disease.
Batten disease has a devastating effect upon children and their families, and we are working to understand these diseases better and to develop ways to treat them successfully. These effects of disease have always been thought of as being mostly upon the brain and spinal cord, but we are learning that the rest of the body is also affected. We have recently shown that in addition to the central nervous system, the bowel, peripheral nerves and muscles are all also impacted by disease. This project will use this new perspective to systematically explore why children with Batten disease have difficulty in swallowing, something that impairs life quality and is life-threatening. This is a crucial first step in being able to treat this significant and distressing problem.
We will first study parts of the brainstem, a primitive part of the brain that sends nerves to muscles of the tongue and throat and helps to control swallowing. We will then explore the nerves themselves and their connections with muscles that help us swallow, including the esophagus, the muscular tube that carries food and liquids from the throat to the stomach. Our work so far suggests that all of these structures are likely compromised in mice that have CLN1, CLN2, and CLN3 disease. We will now define when these underappreciated effects of disease start and how they worsen over time. Together with functional studies of swallowing, the information we learn will be crucial for being able to judge whether attempts to treat swallowing defects have been successful.
The BDGRI thanks Drew’s Hope and Noah’s Hope – Hope 4 Bridget for partnering with us to support this project.
TPP1 Dried Bloodspot assay feasibility testing for UK Newborn Screening
| CHIEF INVESTIGATOR: | Wendy Heywood, PhD |
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| AFFILIATION: | Institute of Child Health, UCL, London, UK |
| AMOUNT: |
USD $49,528
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Heywood
Wendy Heywood is a GOSH BRC Principal Research Fellow and group leader in Translational Mass Spectrometry. She is also an Honorary Clinical Biochemist at Great Ormond Street Hospital and the UCLH National Hospital and Director and co-founder of the UCL spin out Guilford Street Laboratories.
Dr. Heywood’s research group focuses on developing biomarkers in Lysosomal Storage Disorders such as Neuronal Ceroid Lipofuscinosis (Battens disease), Niemann Pick C disease, and the Glycosphingolipidoses disorders (Fabry, Gaucher & Krabbe disease).
With expertise in proteomics and lipidomics for biomarker discovery and understanding disease mechanisms, Dr. Heywood’s group develops novel targeted multiplex assay panels for clinical applications such as clinical trials and supporting the development of novel therapies. This includes the creation of the Immuno TADA platform an innovative multiplex anti-drug antibody assay for Fabry disease which is now in commercial development to be offered through the NHS. The group has particular focus on supporting active collaborations with clinical partners to develop and streamline the translation of novel biomarkers.
CLN2 disease is a rare childhood disorder that results in progressive neurodegeneration. With the introduction of treatment for CLN2 disease, there is the need to identify patients as early as possible to enable the best outcome before the disease progresses too far. Newborn screening (NBS) in the UK is only performed for treatable diseases where there is a viable test. CLN2 disease now falls under that category and has been acknowledged as an inborn error of metabolism that should be prioritised for inclusion into NBS screening programmes (Jones et al 2022).
In order to get the UK NBS committee to consider CLN2 disease for inclusion a viable test needs to be demonstrated that can detect a CLN2 patient from a dried blood spot (DBS). DBS activity assays for TPP1 (the enzyme deficient in CLN2 disease) have been developed in other countries (Lukacs et al 2019) and could be suitable for feasibility testing for UK NBS screening. The UCL inborn errors in metabolism group is based at UCL Great Ormond Institute of Child Health and works closely with clinicians and healthcare professionals in Great Ormond Street Hospital (GOSH). We have expertise in specialist clinical assay development and perform routine analysis for the hospital and industry. We would like to set up and develop this assay in our laboratory and test its feasibility for NBS using DBS collected from CLN2 patients at GOSH. These will be collected by Prof Paul Gissen who is one of the lead clinicians at GOSH who treats the CLN2 patients. The assay will be assessed against non-CLN2 DBS samples collected by the Great Ormond Street chemical pathology department.
Repurposing drugs for Batten disease
| CHIEF INVESTIGATOR: | Professor Sara Mole, PhD |
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| AFFILIATION: | UCL Great Ormond Street Institute of Child Health, London, UK |
| AMOUNT: |
USD $65,000
|
Mole
Sara Mole is Professor of Molecular Cell Biology at University College London where she is Head of the Inborn Errors of Metabolism Section at UCL Great Ormond Street Institute of Child Health. She has an international reputation for research on Batten disease. This began with identifying the genes that cause Batten disease, leading to the setting up and curation of the NCL gene mutation databases. Her lab currently has a focus on research to generate knowledge that supports the development of new therapeutic approaches. Dr Mole is also UCL Envoy for Gender Equality, and a champion for gender equality in UCL, the UK, and internationally.
We want to develop lifesaving or quality-of-life enhancing drugs for Batten disease. Ideally, these will be easy to administer (such as swallowing a pill), will reach and treat all parts of the body, and enhance or complement other therapies that target only the brain or eyes to prevent loss of vision. Any new drug has to be tested for safety and effectiveness, and the appropriate dose worked out for children. Repurposing drugs that have been used before in people allows a fast translation from bench to bedside, as their safety is known and they have often been used extensively in the clinic without serious side effects.
We screened more than 2000 drugs that are approved for use in people and showed that one being used in the clinic for something unrelated to Batten disease also works to correct defects in cells from patients with different types of Batten disease. The next step is to test this drug in a small animal model of Batten disease. The mouse model of CLN5 disease is ideal for this as changes due to the disease can be seen easily within a few months. We have already used this mouse model to test the effectiveness of a second drug that is already being used for diseases similar to Batten disease and showed that this increases life span and improves how the mice move and prevents the death of brain cells and loss of weight. We will now do the same for our new drug of interest.
By the end of the study, we will know if both drugs work equally well or if one is much better than the other. These two drugs affect different pathways in the body so we will also test the mouse model improves faster when taken together.
The study will produce the data needed to support the further testing required to build a case for a clinical trial using the new drug or both drugs together.
The BDGRI thanks the Beyond Batten Disease Foundation for partnering with us to support this project.
Transcutaneous Vagal Stimulation in fear related episodes of dysautonomic sympathetic overactivity in CLN3 patients
| CHIEF INVESTIGATOR: | Professor John Østergaard, DMSci |
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| AFFILIATION: | Centre for Rare Diseases, Department of Children & Youth, Aarhus University Hospital, Denmark |
| AMOUNT: | USD $50,000 |
Østergaard
John Østergaard is the Senior Scientific Consultant at Aarhus University Hospital and the Founder and Senior Consultant of Center for Rare Diseases. He has been a Professor in Child Neurology for 15 years at the University of Aarhus, Aarhus, Denmark.
His research is focused on congenital developmental disability disorders and genetically derived neurodegenerative diseases, especially diseases leading to childhood dementia. Since 1996, a special interest and scientific focus has been on clinical aspects of the Neuronal Ceroid Lipofuscinoses; not just what happens inside the brain, but also what happens outside the brain, like the heart, peripheral nervous system, and the autonomic nervous system. Recently, he demonstrated a time-wise correlation between fearful behavioral changes and episodic sympathetic hyperactivity in adolescents and adults with CLN3 and has now focused on the prevention and treatment of these episodes. So far, he has published more than 200 pair-reviewed papers, more than 20 chapters in Medical Textbooks, and supervised 14 PhD students.
Project deferred. We look forward to sharing an update soon.
More than half of teenagers and adults with CLN3 experience recurring episodes of fearful behavior. These episodes can happen without any clear trigger, but they often occur when the person is uncomfortable, like when exposed to even mildly painful stimuli, hears loud or unpleasant sounds, is in less known surroundings, or when left alone by caregivers or parents. As the affected individual gets older, the episodes tend to happen more often and last longer, sometimes for hours. In the most severe cases, this can increase the risk of early death. Clinically, the episodes look like the non-epileptic seizures that often happen after a severe traumatic brain injury and known as Paroxysmal Sympathetic Hyperactivity (PSH).
Research has shown that after puberty, CLN3 patients have an increased dominance of the sympathetic nervous system (which activates our “fight or flight” response), and this seems indeed to be linked to the fearful behavioral episodes. To investigate this further, we have recently carried out a bedside study measuring heart rate variability (HRV), which is an activity marker of the autonomic nervous system. We discovered that the parasympathetic activity (which should calm the body) decreases right before and during the episodes, returning to normal afterward. It means that just before the episodes happen, there’s a decrease in the activity of the (calming) parasympathetic nervous system leading to a significant hyperactivity of the sympathetic activity. This implies that the adolescent CLN3 person is unable to respond in a balanced manner when affected or threatened by unpleasant situations. This results in a transient sympathetic hyperactivity and therefore the CLN3 adolescent, when feeling discomfort, reacts with an exaggerated fearful behavior.
With this in mind, we are now looking into treatments to prevent or reduce these episodes. One idea is to stimulate the vagal nerve, which in healthy people increases parasympathetic activity and reduces sympathetic activity. A gentle non-invasive method called transcutaneous auricular vagal nerve stimulation (taVNS) involves small electrodes placed on a small external part of the left external ear where a branch of the vagal nerve is located. This sends signals to the brain areas responsible for emotional regulation, including the fear response. We therefore believe that taVNS could be an effective and gentle method to treat and/or even prevent these episodes.
The BDGRI thanks the Beyond Batten Disease Foundation for partnering with us to support this project.
Exploring the efficacy of bis(monoacylglycero)phosphate synthesis pathway intermediates in treating CLN8 Batten disease in preclinical models
| CHIEF INVESTIGATOR: | Kasparas Petkevicius, PhD |
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| AFFILIATION: | MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK |
| AMOUNT: | USD $50,000 |
Petkevicius
Kasparas Petkevicius is a biochemist specialising in phospholipids. He earned a BSc in Biochemistry from the University of Bath in 2013. He then completed a Wellcome Trust PhD programme at the University of Cambridge in 2018, studying macrophage phospholipid metabolism in obesity. After a postdoctoral fellowship at AstraZeneca in Sweden, where he investigated novel proteins involved in phospholipid metabolism, in 2021 he advanced to the role of Associate Principal Scientist, focusing on metabolic disease drug discovery. In 2023, he joined the MRC Mitochondrial Biology Unit as a ‘Springboard to Independence’ fellow, leading a research group on mitochondrial phospholipid metabolism.
Batten disease is a rare and severe genetic disorder that primarily affects children, causing progressive loss of brain function, motor skills, and vision, ultimately leading to premature death. This proposal focuses on one type of Batten disease called CLN8 Batten disease, which is caused by mutations in the CLN8 gene. Recent research from our lab has discovered that the CLN8 protein plays a crucial role in making a molecule called bis(monoacylglycero)phosphate (BMP), which is essential for the healthy function of cell structures called lysosomes. Lysosomes act as the “recycling centers” within cells, breaking down and disposing of cellular waste. Without sufficient BMP, lysosomes cannot work effectively, leading to the buildup of waste materials that damage cells and contribute to the symptoms of Batten disease.
Our research aims to find a new treatment approach by directly providing BMP or related molecules to affected cells, essentially bypassing the missing function of the CLN8 protein. We hypothesize that by supplementing these BMP-related molecules, we can restore normal lysosome function, slow down disease progression, and improve quality of life for patients with CLN8 Batten disease. The project has three main steps. First, we will test BMP-related molecules in simple lab-grown human cells lacking CLN8 gene, in order to see if they can help restore lysosome function. Next, based on the results obtained in simple cells, we will refine these tests in lab-grown human neurons (nerve cells), which are more relevant to the brain damage caused by Batten disease. Finally, we will move on to tests in mice that have been genetically modified to mimic human CLN8 Batten disease. By examining the effects of these molecules in the brain and liver of these mice, we hope to understand how effective this treatment could be in CLN8 Batten disease patients.
Integrative -Omics Profiling and Biofluid Biosignature Development in Large Animal Models of CLN1, -2, -3, -5, and -6
| CHIEF INVESTIGATOR: | Jill Weimer, PhD |
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| AFFILIATION: | Sanford Research, University of South Dakota, USA |
| AMOUNT: | USD $55,000 |
Weimer
Jill Weimer is a developmental neuroscientist and oversees the management and continued development of the translational arm of Sanford Research in Sioux Falls, South Dakota. She started at Sanford Research in 2009, and her research program focuses on the molecular mechanisms mediating the development of the cerebral cortex and how disruption in these processes can lead to a whole host of neural pediatric disorders, including Batten’s disease and Neurofibromatosis Type 1. Work in Dr. Weimer’s lab helped lead to the first-ever gene therapy trial programs for CLN3 and CLN6 – Batten disease. In June 2019, Dr. Weimer joined the Amicus Therapeutics team as the Senior Vice President of Discovery Research and Gene Therapy Science and now serves as the Chief Science Officer. She plays a unique dual role holding leadership positions with both Sanford Research and Amicus, in addition to leading her research lab. Dr. Weimer grew up in north central Missouri and moved to upstate New York where she received her bachelor’s degree and Ph.D. in neuroscience from the University of Rochester. She completed her postdoctoral training in the Neuroscience Research Center at the University of North Carolina in Chapel Hill with a focus on developmental neuroscience. Dr. Weimer also serves as a scientific advisor to a number of rare disease foundations as well as serving as the President of the Alumni Council for her alma mater, the University of Rochester School of Medicine and Dentistry.
Biomarkers are measurable signs that help doctors diagnose diseases, track how they progress, and see how well treatments are working. They can include a mix of biological data from lab tests conducted on blood samples or biopsies, results from imaging tests such as x-rays, MRI and CT scans, physical symptoms, and even genetic information. Biomarkers are used daily in healthcare for common diseases, such as body temperature for fevers which often indicates an infection, or cholesterol which can be a risk indicator for heart disease. Identifying biomarkers for rare diseases can be challenging due to the small number of patients, wide variations in disease symptoms and progression, and in many cases, unknown underlying causes. However, identifying a biomarker or set of biomarkers for rare diseases may be essential in speeding up development of new treatments. The FDA has a program that speeds up the approval process for new drugs aimed at serious conditions where there is an unmet need. This program allows the use of biomarkers that may predict a beneficial change as stand-ins for actual measures of a positive health change in a patient, making it easier to test new treatments.
To find these useful biomarkers, we plan to study fluid samples from large animals with specific genetic conditions that model certain types of NCL diseases. Advanced lab techniques will be used on these samples to identify substances that change significantly in sick animals compared to healthy ones at different stages of disease. The results will be combined with other data, such as levels of proteins or fats, genetics, and other characteristics to create a scoring system that reflects the type and stage of the disease and can track its progression without invasive procedures. Instead of relying on single biomarkers, we hope to develop a combined scoring model that uses multiple markers to give a clearer picture of health status and disease progression. Ultimately, this work in this proposal aims to create reliable biomarkers that can help improve clinical trials and provide better ways to monitor and manage diseases like NCL.
The BDGRI thanks Drew’s Hope and Noah’s Hope – Hope 4 Bridget for partnering with us to support this project.