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start to analyze the mechanisms that underlie the reappearance of FD lesions in mice after anti-mouse RANKL antibody withdrawn, to better understand the “rebound” that occurs after denosumab discontinuation.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.

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.

Model systems to study the Bloom Syndrome Helicase in Homologous Recombination

Awardee: Roger Greenberg

Institution: University of Pennsylvania

Awarded: $100,000

Funding Period: September 1, 2022 - August 31, 2024

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Project Summary:

Bloom Syndrome arises due to inherited mutations in the gene that encodes the BLM helicase. Patient cells experience myriad alterations to their DNA due to deficiency in specific aspects of a DNA repair process known as homologous recombination. We have developed systems that allow us to identify the function of the BLM helicase in DNA repair at a defined region of the human genome. We have used these approaches to publish high impact papers during this funding period that describe the role of BLM in DNA repair. In year two of this project, we expect to gain a better understanding of how BLM helicase acts to direct DNA repair and strategies to bypass the need for BLM when mutations in the BLM gene arise.

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Publications:

Zhang T, Rawal Y, Jiang H, Kwon Y, Sung P, and Greenberg RA. Break Induced Replication Orchestrates resection dependent template switch. Nature 619(7968):201-208, 2023.

Identification and characterization of factors that suppress Bloom syndrome genomic instability

Awardee: Maria Jasin

Institution: Memorial Sloan Kettering Cancer Center

Awarded: $100,000

Funding Period: September 1, 2022 - August 31, 2024

Development of Normal and Tumor Organoids from Bloom Syndrome to Evaluate Responses to Pharmacological and Genetic Perturbations

Awardee: Nathan Ellis

Institution: University of Arizona

Awarded: $150,000

Funding Period: September 1, 2022 - August 31, 2024

Multi-organ Gene Therapy for Bloom Syndrome

Awardee: Amy Wagers

Institution: Harvard University

Awarded: $100,000

Funding Period: September 1, 2022 - August 31, 2024

Molecular mechanisms of EPHB4 pathogenesis – towards new treatment development for lymphatic anomalies

Awardee: Silvia Martin Almedina

Institution: St. George’s University of London

Awarded: $25,000

Funding Period: September 1, 2022 - August 31, 2023

Analysis of a new therapeutic approach to inhibit osteolysis in Gorham-Stout Disease

Awardee: Michela Rossi, PhD

Institution: Bone Physiopathology Research Unite, Bambino Gesu Children’s Hospital, Rome

Awarded: $25,000

Funding Period: September 1, 2022 - August 31, 2023

iPSCs for Fibrodysplasia Ossificans Progressiva

Awardee: Danielle Kerkovich

Association: International Fibrodysplasia Ossificans Progressiva Association

Funding Period: July 27, 2022

iPSCs for Bloom Syndrome

Awardee: Mary Campbell

Association: Bloom Syndrome Association

Funding Period: July 27, 2022

iPSCs for Shwachman-Diamond Syndrome

Awardee: Eszter Hars

Association: Shwachman-Diamond Syndrome Alliance

Funding Period: July 27, 2022

Mouse Model for CACNA1A gene mutations and related neurodevelopmental disorders

Awardee: Lisa Manaster

Foundation: CACNA1A Foundation

Funding Period: May 13, 2022