Defining APBD pre-clinical biomarkers and assessing a therapy in an APBD mouse model.

Awardee: Matthew Gentry

Institution: University of Florida

Grant Amount: $49,677.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Glycogen is a key energy storage macromolecule in cells. However, the accumulation of aberrant glycogen in the brain drives devastating diseases like Lafora disease (LD) and Adult Polyglucosan Body Disease (APBD). The Gentry laboratory has >15 years of experience defining disease mechanisms for LD and developing pre-clinical therapies and biomarkers that are being translated into the clinic. The Akman laboratory has >15 years of experience defining disease mechanisms for APBD and developing pre-clinical therapies. In this proposal, they will combine efforts to: 1) define the brain metabolic perturbations in an APBD mouse model to identify APBD biomarkers and 2) assess an enzyme therapy as a pre-clinical APBD treatment in the same mouse model. This project brings together two laboratories with non-overlapping expertise in studying glycogen storage diseases to tackle critical questions for the APBD community.

Establishing autophagy inducers as novel therapies in cellular and animal models of Beta-propeller Protein-Associated Neurodegeneration (BPAN)

Awardee: Bertrand Mollereau

Institution: Ecole Normale Supérieure of Lyon

Grant Amount: $69,775.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

beta-propeller associated neurodegeneration (BPAN is the most recently identified sub-type of neurodegeneration with brain iron accumulation (NBIA) and there are currently no effective treatments for the disease. BPAN is caused by mutations in an autophagy gene WDR45. Autophagy is an important mechanism regulating neuron survival. Defective autophagy has been observed in several BPAN cellular and models and it was proposed that reduced autophagy could be responsible for neurodegeneration in BPAN patients. Hence, identification of novel therapeutics that restores a functional autophagy constitutes research priority. We have previously identified small molecule compounds that correct autophagy in cultured cells isolated from BPAN patients. We now propose to further develop test and validate the most promising hits. For this purpose, we have developed an animal fly model of BPAN disease exhibiting hallmarks of the disease, such as autophagy defect, iron accumulation, neurodegeneration and locomotor disorder. We will select the best molecule compounds restoring autophagy in human cells to rescue the cellular and locomotor defects them in BPAN flies. From our study, the most promising compounds will then be ready to be tested in a larger animal, with an ultimate aim of clinical translation and tangible patient benefit as soon as possible.

Targeting Metabolic Homeostasis in Dysfunctional CHM Retinal Pigment Epithelia

Awardee: Kathleen Boesze-Battaglia

Institution: University of Pennsylvania

Grant Amount: $61,760.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Loss of vision due to choroideremia (CHM), a progressive retinal degenerative disease affects 1 in 50,000 males. Advanced imaging modalities have recently documented sub-clinical changes in the retinal pigment epithelia (RPE) of CHM patients. While metabolomic studies demonstrate dysfunctional metabolism in CHM patients characterized by a disruption of lipid homeostasis. Collectively, these observations implicate RPE-mediated metabolic dysregulation resulting from loss of Rab Escort Protein-1 (REP1) as an etiological factor in CHM. The Boesze-Battaglia lab has extensive experience with lipid homeostasis in models of human retinal degenerations. To explore the potential of metabolic pathways as therapeutic targets for CHM, we have analyzed induced pluripotent stem cell (iPSC)-derived retinal cell from CHM patients. Treatment strategies for CHM are limited albeit clinical trials for gene augmentation strategies are underway. The efficiency of such treatments may not be truly appreciated or fully assessed for nearly a decade due to the slow progressive nature of the disease. Therefore, there remains an unmet need to explore other options to preserve the health and integrity of the retina prior to noticeable degeneration of the eye. Our goal is to define metabolic imbalance in CHM RPE in an effort to restore metabolic homeostasis and RPE function using CHM-patient specific cell models.

Using TERT variant-to-function analysis to define cryptic telomere biology disorders in sporadic cancers

Awardee: Coleman Lindsley

Institution: Dana-Farber Cancer Institute

Grant Amount: $62,528.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Impaired telomere maintenance is linked to development of cancer. Inherited mutations affecting telomerase cause short telomeres in all tissues and an increased risk of specific cancers. The goal of this proposal is to define the spectrum and functional impact of inherited TERT mutations in adults with cancer and analyze associations with clinical outcomes. To achieve this goal, we have assembled a cohort of 40,000 adult patients with various cancers, will identify TERT variants in existing DNA sequencing data, and perform comprehensive functional interrogation of cancer-associated TERT variants to define their effects on telomerase function.

Lysosomal-Targeted Strategies for TBCK Syndrome

Awardee: Xilma Ortiz-Gonzalez

Institution: University of Pennsylvania

Grant Amount: $40,000.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

We have recently co-discovered TBCK-encephaloneuronopathy (TBCKE) syndrome. Many of the patients that helped us establish the genetic link to the disease are my patients in the CHOP neurogenetics clinic. Using patients’ cells, we first reported that TBCK mutations alter autophagy, and then showed that there is secondary mitochondrial dysfunction (ie cellular energy production) in patient cells. We suspect the abnormal mitochondria are due to dysfunctional recycling within the cell, which ultimately happens in the lysosome. Our data suggests that targeting the lysosome (by promoting acidification) can rescue the mitochondrial deficits in TBCK cells. We now propose to further investigate the basis of the lysosomal dysfunction as a potential therapeutic target for TBCK syndrome. We specifically will test 2 strategies that have clinically available (or soon to be available) drugs, to expedite the translation of our preclinical research to future potential clinical trials.

Investigating mechanisms underlying cognitive dysfunction in Glut1 deficiency syndrome

Awardee: Maoxue Tang

Institution: Columbia University

Grant Amount: $61,855.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Glucose Transporter-1 deficiency syndrome (Glut1 DS) is a pediatric-onset brain disorder caused by mutations in one copy (haploinsufficiency) of the SLC2A1 (Glut1) gene and therefore low levels of the SCL2A1-coded protein, Glucose Transporter-1. Patients afflicted with Glut1 DS suffer severe epileptic seizures as children and also exhibit delayed cognitive development. Later in life, a debilitating movement disorder develops and predominates. As of yet, there is no truly effective treatment for Glut1 DS. Moreover, it is unclear how low Glut1 protein causes brain dysfunction. In this project, we wish to understand how low Glut1 results in impaired cognition. We suspect that lactate, a downstream product of brain glucose, is a key mediator of Glut1 DS disease. Low brain glucose in Glut1 DS is thought to reduce levels of brain lactate. Since brain lactate is the preferred energy substrate of cerebral neurons, these neurons are starved. Consequently, they are unable to efficiently connect and communicate with one another. These ideas will be investigated in well-established model mice we have created in the laboratory. At the end of the project, we expect to have a better understanding of how low Glut1 affects cognition and how impairments in cognition correlate with altered brain structure. The project is also expected to identify molecules that rely on adequate brain glucose (and lactate) to ensure that the cerebral circuitry is properly established. Consequently, at the conclusion of this project, we expect to be in a better position to identify therapeutic points of intervention in our quest to treat Glut1 DS effectively and safely.

Investigating key clinical aspects of Fibrous dysplasia of bone in a transgenic mouse model (EF1a-GsαR201C mice) of the disease: pain, effect of anti-resorptive treatments and “rebound” phenomenon.

Awardee: Mara Riminucci

Institution: Department of Molecular Medicine, Sapienza University of Rome

Grant Amount: $80,000.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

We will continue our studies on the link between bone resorption and bone pain in Fibrous dysplasia (FD) of bone. Thanks to our MDBR-21-110-FD award we set up in our laboratory three tests widely used to evaluate the presence of pain in mice (pain-like behavior) and, through these tests, we have demonstrated that our FD transgenic mice are a good model to study bone pain associated with FD. Then we have demonstrated that treatments that inhibit bone resorption [anti-mouse RANKL antibody (an equivalent of denosumab) and Zoledronic acid (a potent bisphosphonate)] improved mouse behavior in the different tests, thus suggesting a reduction of bone pain. In this project we will continue these studies and will analyzed the distribution of nerve fibers (involved in pain transmission) within FD lesions. In addition, we will start to analyze the mechanisms that underlie the reappearance of FD lesions in mice after anti-mouse RANKL antibody withdrawn, to better understand the “rebound” that occurs after denosumab discontinuation.

Pain and Analgesic Mechanisms in a Mouse Model of Fibrous Dysplasia

Awardee: Anne-Marie Heegaard

Institution: University of Copenhagen

Grant Amount: $80,000.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Pain is common and difficult to control symptom for many fibrous dysplasia patients. We have investigated a mouse model of fibrous dysplasia and found that the mice display pain-related behaviors. We have also found that the mice with painful fibrous dysplasia have changes in the peripheral nervous system and an increased expression of factors, which might contribute to the pain. Therefore, the goal of this project is to use the fibrous dysplasia mouse model to further investigate the mechanisms underlying pain in fibrous dysplasia and to test new treatment avenues.

Editing the epigenome: Curing SYNGAP1 heterozygosity

Awardee: Elizabeth Heller

Institution: University of Pennsylvania

Grant Amount: $65,705.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

SynGAP1 syndrome occurs when a child is born with only one functional copy of the SynGAP1 gene. One approach to correct and cure this syndrome is to further activate the functional copy of the SynGAP1 gene, in order to compensate for the mutated copy. A major benefit of this approach is that it is independent of the specific mutation on the dysfunctional copy, and therefore can be utilized by all children with SynGAP1 syndrome. In order to develop a therapy that activates the functional copy of the SynGAP1 gene, we will first uncover the cellular mechanisms that govern SynGAP1 gene activation. Next we will develop tools to artificially activate SynGAP1 in the brain. Our goal is to design an intervention that is functional at all stages of development, for all SynGAP1 children.

Brain Penetrant Therapeutic Proteins for SETBP1 Haploinsufficiency Disorder

Awardee: Barbara Bailus

Institution: Keck Graduate Institute

Grant Amount: $45,832.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

SETBP1-HD is a neurodevelopmental disorder caused by a decreased amount of the SETBP1 protein, which plays a role in neuronal development, specifically in epigenetic modification. A potential treatment for this disorder would involve increasing SETBP1 levels in the brain. Several other disorders have been successfully treated by using a similar approach of directly providing the absent or reduced protein to the relevant tissue. This proposal aims to increase the levels of SETBP1 by creating novel therapeutic proteins that would have the ability to enter the brain from a peripheral injection through the use of a novel cell penetrating peptide (CPP). The CPP would act as a “keycard” to the brain allowing for the therapeutic proteins to enter. The CPP would make the potential treatment minimally invasive, titratable and with the ability to be removed if necessary. This proposal would test the therapeutic proteins in cellular models, with the aim to leverage this data to a future mouse study.

Deciphering the neurobiological pathways involved in heterogenous SETBP1 haploinsufficiency disorder using human brain organoids and transcriptomics

Awardees:

Simon E Fisher: Max Planck Institute for Psycholinguistics, The Netherlands

Maggie MK Wong: Max Planck Institute for Psycholinguistics, The Netherlands

Bregje W van Bon: Radboud University Medical Center, The Netherlands

Grant Amount: $45,832.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

SETBP1-haploinsufficiency disorder is a rare disorder caused by DNA changes that lead to a decreased amount of the SETBP1 protein. Individuals with SETBP1-haploinsufficiency disorder show moderate-to-severe speech and language impairments, wide variability in intellectual functioning, hypotonia, vision impairment, and behavioral problems such as attention/concentration deficits and hyperactivity. To date, we still know little about how the SETBP1 protein works, and why insufficient amounts of this protein affect the human brain, leading to a disorder. Our research aims to utilize the informative tools that we have established in the laboratory to study the molecular and cellular pathways that are altered in SETBP1-haploinsufficiency disorder, and to understand how these relate to the clinical features of patients. Ultimately, we hope that analyses of SETBP1 (dys)function in the laboratory can help towards therapeutic development for the disorder.

Development of proof-of-concept Pitt-Hopkins Syndrome therapy by upregulation of TCF4 transcriptional activity

Awardee: Tonis Timmusk

Institution: Tallinn University of Technology

Grant Amount: $71,650.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Pitt Hopkins syndrome (PTHS) is a genetic developmental disorder that severely affects cognitive, motor and social development. PTHS has been diagnosed in less than 1000 people in the world. It is caused by mutations in one of the two alleles of a gene called TCF4, which encodes a protein named Transcription Factor 4. Most of the mutations found in TCF4 gene in PTHS patients are of de novo origin meaning that the mutation is not present in the parents. TCF4, as other transcription factors, is a protein that regulates the expression of genes. In the nervous system TCF4 plays an important role in proliferation, differentiation and migration of neurons, as well as brain plasticity. Upregulation of the transcriptional activity of the functional TCF4 protein could improve the symptoms of PTHS. The goal of the current project is to develop a method to upregulate TCF4 activity levels by targeting TCF4 co-regulators.

Fingerprinting a multiomics biomarker profile in patients with STXBP1-RD

Awardee: Pasquale Striano

Institution: University of Genoa

Grant Amount: $87,125.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Mutations in STXBP1 gene lead to a complex and severe neurodevelopmental disorder (STXBP1-related disorders, -RD), with symptoms including intellectual disability, epilepsy, movement and behavioral disorders, and gastrointestinal (GI) symptoms. There is no cure to date, but targeted therapies for STXBP1 are under investigation. However, the variability of symptoms and severity of STXBP1-RD makes it challenging to evaluate the effect of a treatment during a clinical trial, so that we need to identify biomarkers of the disease that can be measured. We will explore these biomarkers in the metabolome and gut microbiome of patients with STXBP1-RD. Gut microbiome is the pool of microorganisms that live in our gut and constantly interacts with our organism, including with our brain (gut-brain axis). Bacteria produce a lot of substances that join our metabolome, which is the whole pool of substances present in our blood and produced or introduced in our organism. Alterations in microbiome and metabolome can be identified in many health conditions, including autism and epilepsy. We aim to identify specific alterations in the microbiome and metabolome profiles of patients with STXBP1-RD, that can be further investigated as biomarkers and as therapeutic targets.

Assessing and quantifying gait problems in patients with STXBP1-related disorders using three-dimensional gait analysis

Awardee: Sarah Weckhuysen

Institution: VIB-CMN, University of Antwerp

Grant Amount: $87,125.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

While STXBP1-related disorders (STXBP-RD) were initially described as being associated with seizures and intellectual disability (ID), the phenotypic spectrum has since then considerably broadened. We now know it includes ID without seizures, behavioral problems such as autism, and a range of movement disorders with often prominent gait problems, which all significantly impact quality of life of both the patients and their caregivers. To date, treatment of STXBP1-RD is largely limited to seizure control and there is a lack of guidelines for multidisciplinary revalidation, including motor revalidation. In this project, we aim to combine our expertise with STXBP1-RD with the available expertise in our university with gait analysis in other neurodevelopmental syndromes such as Dravet syndrome, to characterize the nature and evolution of gait abnormalities and functional mobility in patients with in STXBP-RD. We will do this in a semi-quantitative way using three-dimensional gait analysis in a cohort of 30 children and adults with STXBP-RD. We intend to use the information obtained to develop guidelines for motor revalidation for individuals with STXBP1-RD. Furthermore, the data conducted in this study will contribute to the identification of non-seizure related clinical endpoints related to motor function, a crucial step to ensure successful clinical trials in the future.

Dopamine in Lesch-Nyhan Disease

Awardee: Jasper Visser

Institution: Radboud University Medical Center, Nijmegen, The Netherlands

Grant Amount: $85,779.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

In Lesch-Nyhan disease (LND), it is unknown why the loss of a very generic protein that is present in all cells of the body causes such a specific brain dysfunction with abnormal movements and self-injury. It is thought that brain cells that use the neurotransmitter dopamine to pass on signals to other brain cells are particularly affected in LND, but it is not known whether these are the only brain cells that are affected. This project investigates in a mouse model for LND whether repairing these dopamine neurons alone would be sufficient to prevent or treat the brain abnormalities in LND. If that is the case, they could serve as the primary target for future therapies.

Publications:

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease

PET Radiotracer development based on existing ATM-inhibitors

Awardee: Jacob Hooker

Institution: Massachusetts General Hospital

Grant Amount: $116,172.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Ataxia-telangiectasia (A-T) is a rare autosomal recessive genetic disease that involves progressive neurodegeneration (cerebellar atrophy), immune deficiency, lung problems and a strikingly high increased risk of cancer. Children with A-T start life with almost normal motor function but then lose muscle control and balance so that speech, eye-tracking and swallowing become much more difficult, and they usually need to use wheelchairs by age nine. Multiple therapeutic strategies are being pursued clinically but there is no direct functional restoration measure of ATM, the PIKK (PI3K-like protein kinase) available for therapeutic monitoring in the brain. Our hypothesis is that functional ATM presents a binding site for a small-molecule-based ATM-inhibitor and thus binding of the inhibitor can be used as a proxy measure of the functional concentration of ATM. By labeling ATM-inhibitors with a positron emitting isotope, it thus may be possible to image the amount of functional ATM in the brain using positron emission tomography. We will synthesize and radiolabel a series of ATM-inhibitors for evaluation of this functional biomarker concept.

Identifying Unmet Care and Communication Needs of Families Affected by Complex Lymphatic Anomalies

Awardee: Bryan Sisk

Institution: Washington University School of Medicine

Grant Amount: $53,460

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Complex lymphatic anomalies (CLAs) are a group of rare disorders associated with abnormal lymphatic development that arise in infants and children. These disorders can be disfiguring, painful, and even life-threatening. In our clinical experiences, families affected by CLAs have described multiple barriers to care and communication, such as difficulty accessing care from CLA experts, persistent uncertainty about the diagnosis and long-term consequences, insufficient information to guide decisions, and the necessity of persistent parental advocacy to ensure the child receives adequate medical care. However, no researchers have explored or categorized the needs or barriers experienced by these families. Without this critical information, we cannot provide guidance to clinicians, patients, parents, or advocacy groups on how to best support these families to overcome care and communication challenges. Furthermore, this foundational knowledge is necessary to support the development of interventions and systemic changes to improve care for these families. In this study, we will characterize the care and communication needs of families affected by CLAs and identify resources and coping strategies from the perspectives of parents using qualitative semi-structured interviews (Aim 1). We will also assess the psychosocial wellbeing of parents and the quality of communication using survey methodology (Aim 2). To disseminate findings and seek feedback from the CLA community (Aim 3), we will host separate interactive webinars with the Lymphangiomatosis and Gorham’s Disease Alliance (LGDA) and the Chan-Zuckerberg Institute (CZI) Lymphatic Researchers Network. These findings will be essential to improve care and ensure that scientific discoveries translate to actual clinical benefits for families affected by CLAs.

Novel, point of care biomarker to detect pre-clinical flares for people living with fibrodysplasia ossificans progressiva (FOP)

Awardee: Nezihi Murat Karabacak

Institution: Massachusetts General Hospital

Grant Amount: $64,000

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Fibrodysplasia ossificans progressiva (FOP) is a severely debilitating condition with no accurate and clinically applicable biomarkers or imaging approaches. Our overall goal is to develop a novel, non-invasive assay to detect the initiation and progression of FOP. We will define a series of novel blood-based biomarkers specific for monitoring heterotopic ossification predicated in people living with FOP. As a result, we will establish an innovative way to detect and evaluate progression and monitor treatment outcomes for this disease process.

Understanding the role of inflammation in MPSIIIA disease to identify therapeutic approaches for older patients without treatment options

Awardee: Brian Bigger

Institution: University of Manchester

Grant Amount: $64,015

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Many older patients with mucopolysaccharide diseases are ineligible for new treatment trials, and those with brain disease, such as type IIIA, have no current treatments available. To address this gap, we want to explore in the mouse model of MPSIIIA, the observed decline in cognition that follows repeated rounds of viral infection in patients and has been described in many dementias. Our aim is to first see if these effects can be recapitulated in the MPSIIIA mouse model, and later to develop novel immunotherapies to treat it. There are several drugs already available that may be re-purposable to this end, potentially offering rapid relief for MPS patients from behavioural and cognitive aspects of disease

CNS disease severity assessment with quantitative neuroimaging

Awardee: Igor Nestrasil

Institution: University of Minnesota

Grant Amount: $64,645

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

This project aims to find the underpinnings of brain magnetic resonance imaging (MRI) clinical/radiological severity in mucopolysaccharidosis type I (MPS I) and relate these findings to quantitative MRI outcomes. These links may ease the process of the central nervous system (CNS) disease severity assessment in the clinical setting.