Genetic basis of neuroendocrine cell hyperplasia of infancy

Awardee: Nadia Nathan

Institution: Sorbonne University and Inserm

Grant Amount: $87,145.00

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

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Summary:

Material and methods: Patients will be included in the RespiRare network (Fabre et al. 2022). Patients with a NEHI diagnosis attested by the RespiRare multidisciplinary team (MDT) meeting will be selected. After appropriated consents of the parents, a trio (patient and his two unaffected parents) whole genome sequencing (WGS) will be performed. The identified variants will be studied in terms of in silico pathogenicity and relevance in the context of NEHI pathophysiology. The following gene variants will be selected for comparison between the families: those segregating as new mutations only occurring in affected children and those segregating as recessive traits transmitted from each parent.

Expected results: Identifying molecular causes or predispositions for NEHI is a crucial step in studying the pathophysiology of the disease. This could highlight new pathways of interest that could allow the development of targeted treatments.

Exploring adjuvant immunotherapy to treat lymphangioleiomyomatosis

Awardee: Katharina Maisel

Institution: University of Maryland, College Park

Grant Amount: $75,110.00

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

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Summary:

Lymphangioleiomyomatosis (LAM) is a rare lung diseases that causes cystic destruction of the lungs caused by the abnormal growth of smooth-muscle-like LAM cells that have cancer-like features. To date, rapamycin is the only FDA approved treatment for LAM and this treatment is not a cure. Additionally, about 30% of patients do not respond to the treatment. Therefore, new therapeutic avenues are desperately needed. We and other have recently shown that LAM may cause suppression of the local immune response, similar to cancer, and that re-activating this immune response through checkpoint inhibitor or CAR T cell therapies can enhance survival in a murine model of LAM. Immune adjuvants are another immunotherapy currently under investigation for cancer treatments. We have found that one particular adjuvant, CpG, which activates toll-like receptor 9 (TLR9) on antigen presenting cells can enhance survival in murine LAM. However, this survival is incomplete and thus further investigation is necessary. We have found that repeated dosing of CpG causes an overall reduction of immune cell recruitment to the lungs but does not reduce immunosuppressive regulatory T cells. Repeated TLR stimulation on immune cells can lead to ‘TLR tolerance’, in which the cells become less responsive to the stimulus over time. We hypothesize that TLR tolerance is one of the reasons for incomplete survival after CpG treatment in LAM. Research has also shown that spacing out TLR stimulating treatments or alternating the specific TLR that is stimulated may reduce TLR tolerance. Thus, we will investigate the mechanisms of TLR tolerance in LAM and explore alternative treatments to further increase survival. Overall, this proposal will shed new light onto mechanisms of immunosuppression in LAM and also define new treatment avenues for LAM. Furthermore, this work is the first to use adjuvant immunotherapies as treatments for neoplastic growths with loss of TSC expression and could thus open up the use of these treatments for diseases beyond LAM. Finally, understanding the interplay of immune cells, LAM cells, adjuvant immunotherapies, and loss of TSC expression could lead to new treatment targets/strategies for LAM and other diseases for which adjuvant immunotherapies is used.

Glucan fingerprint as biomarker in Adult polyglucosan body disease (APBD)

Awardee: Berge Minassian

Institution: UT southwestern medical center

Grant Amount: $49,677.00

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

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Summary:

The central paradigm in APBD is excessive and abnormal glycogen in the central nervous system. While it is impossible to non invasively measure this glycogen, we can measure the breakdown products of it in the urine. We devised a technique to profile many of these glycogen breakdown products and showed evidence of being able to use such molecules in the urine of APBD model mice. The current grant will establish testing for other breakdown products in mouse models and patient samples.

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.

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.

Jiang H, Zhang T, Kaur H, Shi T, Krishnan A, Kwon Y, Sung P, and Greenberg RA. BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response. Molecular Cell 84(9):1684-98, 2024.

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