Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis and treatment.

Awardee: Vanessa Fear

Institution: Telethon Kids Institute, University of Western Australia

Grant Amount: $45,733

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

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Summary:

SETBP1 haploinsufficiency disorder presents with intellectual disability, speech impairment and development delay, among other symptoms. There is little information regarding SETBP1 haploinsufficiency disorder and the cellular pathways that lead to disease. This study will use CRISPR gene editing and stem cell neural disease modelling to elucidate cellular pathways that contribute to SETBP1 haploinsufficiency disorder, and identify new treatments.

Toward Structure-based Drug-Discovery for SETBP1

Awardee: Jerome Baudry

Institution: The University of Alabama in Huntsville

Grant Amount: $45,733

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

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Summary:

We will start the first drug discovery pipeline toward finding a pharmaceuticals that can counter the effect of SETBP1 mutations. We will use very powerful computers to predict how mutated SETBP1 interacts with its partners in the cell, and we will identify small molecules that can correct the problems.

Exercise as Medicine in Cystic Fibrosis: A pilot study assessing the impact of a telehealth exercise program on adherence and self-efficacy

Awardee: Stefanie Krick

Institution: The University of Alabama at Birmingham

Grant Amount: $117,655

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

Targeting the shelterin component TINF2 in telomere diseases

Awardee: Suneet Agarwal

Institution: Boston Children's Hospital

Grant Amount: $65,445

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

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Summary:

Telomere biology disorders (TBDs) affect multiple parts of the body, including the blood, lungs, liver and bones. There are no effective treatments that address the life-threatening problems. Telomeres are the ends of chromosomes that ensure ability of cells to keep dividing to replace damaged cells with new healthy ones. In TBDs, genetic mutations reduce telomere length and thus cells cannot regenerate themselves, and the tissues fail causing disease. By studying a particular mutation, we have found that decreasing a protein called TIN2 can increase telomere length in TBD patient cells. In this proposal we will study in depth whether reducing TIN2 could be a viable strategy to restore telomeres in the setting of various mutations that cause TBDs, and also test whether chemicals can be used to achieve this effect. These studies could provide a new therapeutic strategy that could be applied throughout the body for patients with TBDs.

Identification and signaling characterization of GNASR201H/C selective inhibitors for FD/MAS

Awardee: Edward Hsiao

Co-PI: Kelly Wentworth

Institution: University of California, San Francisco

Grant Amount: $53,791

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

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Summary:

Fibrous dysplasia and McCune Albright syndrome (FD/MAS) are severe congenital conditions caused by activating point mutations in the GNAS gene; however, specific molecular tools for directly perturbing GNAS activity in a mutation specific fashion are largely lacking. The overall goal of this proposal is to complete the analysis of a series of promising compounds that we previously identified as likely to specifically bind GNASR201H. We will use a novel human induced pluripotent stem cell model carrying the GNASR201H mutation in the endogenous locus to test our top drug candidates for their ability to block the abnormal cAMP production, and also use physical assays to determine if the inhibition occurs through direct binding to GNAS or by acting on a downstream pathway component. This proposal directly addresses critical needs by identifying promising molecular tools for dissecting GNASR201H function and serving as scaffolds for developing novel therapeutics that directly target GNAS mutations that cause FD/MAS, and validating a new human IPS cell model that will be useful for studies of cellular differentiation and function in FD/MAS. All reagents, compounds, cell lines, and analytical methods are already available through the collaborators and experienced team.

Structure activity relationship studies of compounds to treat FD/MAS

Awardee: Fernando Fierro

Co-PI: Charles Hoffman

Institution: University of California Davis

Grant Amount: $53,791

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

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Summary:

FD lesions contain cells with excess G alpha protein activity that stimulates adenylyl cyclases (ACs), increasing cAMP levels. This disruption of appropriate cell signaling ultimately affects normal bone homeostasis. We propose testing a set of compounds with promising AC-inhibitory activity, with the ultimate goal of developing a therapeutic drug. Our proposal is a collaborative effort among different research groups: Dr. Fierro will identify compounds that reverse GNAS(R201H) or GNAS(R201C) effects in human bone marrow stromal/stem cells. Dr. Hoffman will use yeast to elucidate if the compounds act directly or indirectly on ACs. Dr. Inglese will perform in vitro pharmacokinetic studies with the same compounds.

Unraveling the role of Adiponectin-expressing bone marrow stromal cells in the cellular pathogenesis of Fibrous Dysplasia

Awardee: Biagio Palmisano

Institution: Sapienza University of Rome

Grant Amount: $53,791

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

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Summary:

We have previously shown that osteoclasts, the cells that normally destroy damaged bone to allow its regeneration, play a major role in the appearance and evolution of Fibrous Dysplasia (FD). We know that in growing FD lesions, the number of osteoclasts is abnormally high due to the production of a factor named RANKL by the pathological tissue. However, what we do not know yet is who produces RANKL at the very beginning of the disease, when osteoclasts destroy the healthy bone that will be then replaced by the pathological tissue. Recently, by generating a new Gs(alpha) transgenic mouse model, we have identified the cell type that is involved in this early phase of the disease. In this project, we want to investigate the characteristics of this cell type and the mechanisms through which it produces RANKL, both in the absence and in the presence of the Gs(alpha) mutation. Understanding these points may allow the development of therapies that act specifically on the very first trigger of FD lesions.

Reversing Brain Iron Overload in BPAN by a Natural Small Molecule

Awardee: Young-Ah Seo

Institution: University of Michigan

Grant Amount: $66,366

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

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Summary:

The overall goal of this project is to develop new therapeutic strategies that can reduce brain iron overload and iron-induced neurodegeneration in BPAN patients. We have identified that a natural small molecule is exceptionally effective at promoting iron transport. We have now found that iron accumulates in the BPAN cell model and that the resulting iron overload can be mitigated by this small molecule. Building on these preliminary results, this proposal will extensively characterize the capacity for a small molecule to mobilize excess iron from inside cells and will test the overarching hypothesis that small molecule-mediated iron mobilization can mitigate neuronal cell death in BPAN cell models and patient-derived primary fibroblast cells. Completion of the proposed research will advance our fundamental understanding of the mechanistic underpinnings of brain iron overload in BPAN and will build a foundation for the potential therapeutic use of small molecule mobilizers of intracellular iron.

Membrane homeostasis as potential therapeutic angle in Cohen Syndrome

Awardee: Jens Luders

Institution: Institute for Research in Biomedicine, Barcelona, Spain

Grant Amount: $47,161.00

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

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Summary:

Cohen Syndrome is a rare disease caused by mutations in the VPS13B gene. Patients affected by this disease are born with several disabilities and health problems. For example, children with Cohen Syndrome may develop slowly, have a small head size, intellectual disability, and an overall weak muscle tone. They frequently suffer from a reduction in the number of certain blood cells, which increases the risk of infections, and loss of vision, which becomes worse with age and can lead to blindness. Unfortunately, there is no treatment available for these patients. Since the molecular and cellular functions of the VPS13B gene are still poorly understood, it is unclear how its mutation leads to Cohen Syndrome. This makes it impossible to develop a treatment or therapy. We have recently obtained preliminary data suggesting that Cohen Syndrome may involve defects in primary cilia, hair-like structures on the surface of cells that function as a cell's antenna. They allow cells to receive and respond to signals from their environment and are very important for various developmental processes including formation of the brain and the retina. In this project we will uncover how defects in VPS13B may affect cilium formation and function in three different model systems: cultured cells including cells obtained from Cohen Syndrome patients, retinal tissue grown in a culture dish from patient cells, and zebrafish embryos, which recapitulate many developmental processes that also occur in humans including brain and eye development. Using the same model systems, we will then test if culture supplements or pharmacological treatments may be used to repair ciliary defects. If so, these treatments may be further developed into therapies in the future.

Determination of pathomechanisms and assessment of therapeutic strategies for Cohen Syndrome in patient derived cells and a murine model

Awardee: Muhammad Ansar

Institution: Jules-Gonin Eye Hospital, Ophthalmology Department of the University of Lausanne, Lausanne, Switzerland

Grant Amount: $$115,000

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

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Summary:

Cohen Syndrome (CS) is a rare genetic disease caused by the loss of function of the gene called VPS13B. Individuals with CS suffer from developmental, intellectual, motor, metabolic, immunologic and progressive vision loss problems. In this project we proposed to study and understand how the VPS13B gene functions and how the loss of this gene causes the disease symptoms. At the same time we’ll try to explore and test various treatment options by using cellular and mouse models, with the aim to ultimately find the cure for the CS disease or to at least stop the progressive loss of vision in these patients. Treatment strategies include the use of chemical drugs as well as gene therapy.

High Resolution Ventilation and Perfusion MRI Assessment of Neuroendocrine Cell Hyperplasia of Infancy (NEHI) in Infants and Young Children: Technical Feasibility and Direct Clinical Application

Awardee: Katie Krone

Institution: Boston Children's Hospital

Grant Amount: $41,000

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

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Summary:

Neuroendocrine cell hyperplasia of infancy (NEHI) is a type of childhood lung disease that is very challenging to diagnose because of the lack of specific disease features. Clinical and radiologic features may overlap with other types of lung disease affecting children. Currently, clinicians rely on imaging with high-resolution chest computed tomography (HRCT) and/or tissue diagnosis by surgical lung biopsy in order to identify NEHI in patients who have suggestive clinical signs and symptoms. This diagnostic approach poses risks to the vulnerable pediatric population. HRCT exposes infants and children to potentially harmful ionizing radiation, and often requires sedation to obtain adequate images in younger children. There are also some concerns about the effects of general anesthesia on the developing brain. An additional problem is that HRCT scans are often not specific enough to be diagnostic of NEHI. Given the potential risks of exposure to radiation and anesthesia, and the limitations of HRCT interpretation, new diagnostic strategies are needed that provide insight into the pathophysiology of NEHI, ensure timely, safe and accurate diagnostic information, and improve patient care. High-resolution ventilation and perfusion MRI is new attractive alternative that overcomes the limitations and risks of HRCT and has the potential to provide improved diagnostic information. Thus, the main objective of this study is to prospectively investigate the technical feasibility and clinical utility of high-resolution ventilation and perfusion MRI in infants and young children with clinically suspected or confirmed NEHI.

Spatial Transcriptomics to Identify Cellular Alterations in NEHI

Awardee: W. Adam Gower

Institution: University of North Carolina at Chapel Hill School of Medicine

Grant Amount: $41,000

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

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Summary:

The diagnosis and management of NEHI is complicated by a lack of understanding about the biologic processes at work in the lungs of affected children. Research so far has suggested that NEHI is unique from other forms of childhood interstitial lung disease, and likely involves abnormal function of neuroendocrine cells and other cell types in the smallest airways. We propose to utilize a new technology that will allow use to determine what genetic pathways and biological processes are unique to NEHI lung tissue, using excess lung biopsy material that has already been collected and banked. By understanding which genetic pathways and processes are unique to NEHI compared to children with other lung diseases and healthy controls, we may identify ways to improve diagnosis and perhaps targets for new and unique treatments. Our team has extensive expertise in NEHI and rare lung disease research, access to tissues samples for use, and colleagues who can assist in the analyses needed to complete this project during the award period.

Targeting mTOR signaling to improve neurologic outcomes in MSUD

Awardee: Rebecca Ahrens-Nicklas

Institution: The Children's Hospital of Philadelphia and The University of Pennsylvania

Grant Amount:

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

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Summary:

Maple Syrup Urine Disease arises from a defect in branched chain amino acid metabolism (BCAA), that leads to toxic increases in certain amino acids throughout the body. Dietary therapy and liver transplantation can improve levels of BCAAs; however, unfortunately, patients still have neurocognitive and psychiatric symptoms. Based on work in a mouse model of MSUD, we believe that an inability to use BCAAs as fuel in the brain changes mTOR signaling, an important pathway for neurodevelopment. Other disorders with abnormal mTOR activation are known to result in learning difficulties and psychiatric symptoms. In this application, we plan to study how abnormal mTOR signaling affects the brain in MSUD and to explore new therapeutic approaches aimed at correcting this difference.

Pre-clinical investigation of candidate therapies for NUBPL disease

Awardee: Neal Mathew

Institution: Children's Hospital of Philadelphia

Grant Amount: $50,198

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

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Summary:

The overall goal of this project is to identify lead therapeutic candidates for NUBPL-/- based mitochondrial disease. We hypothesize that therapeutic modeling of NUBPL-/- genetic disease across 3 evolutionarily distinct models will enable identification and optimization of a lead therapeutic regimen to prioritize as a precision medicine that improves health in human NUBPL-/- disease patients.

Untargeted metabolomics to map defects arising in Snyder-Robinson syndrome

Awardee: Ankur Jain

Institution: Whitehead Institute for Biomedical Research

Grant Amount: $74,691

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

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Summary:

Snyder-Robinson syndrome (SRS) is a rare, X-linked genetic disorder caused by mutations in the spermine synthase (SMS) gene. In this project, we will examine how this mutation changes the small molecule metabolite composition of the cell. This work may reveal new disease biomarkers, and may potentially inform intervention strategies.

Measuring neurotransmitter metabolites for biomarker discovery in Mucolipidosis IV

Awardee: Yulia Grishchuk

Institution: MGH

Grant Amount: $64,335

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

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Summary:

Mucolipidosis IV (MLIV) is an ultra-rare lysosomal disorder resulting from inactivating mutations in the MCOLN1, the gene encoding the lysosomal cation channel TRPML1. Patients typically present in the first year of life with delayed developmental milestones and reach a plateau in function roughly equivalent to the 18-20 month-old level. In contrast to other lysosomal disorders, patients with MLIV exhibit a relatively stable clinical course before early adolescence with neurological deterioration first emerging after puberty. Recently, we reported a novel TRPML1 gene replacement strategy that restored motor function when administered to either presymptomatic, newborn MLIV mice or symptomatic mice at 2 months of age. Excitingly, these data suggest that TRPML1 gene therapy may be able to restore motor development in patients with MLIV rather than simply delaying disease progression. However, the time needed for restored developmental processes to produce a clinically meaningful improvement in function in humans is uncertain and will likely exceed the 1 year time period in which traditional FDA approved trials require demonstration of efficacy. As such, there is now a critical unmet need for a clinically tractable biomarker to measure TRPML1 activity restoration in the brain. The goal of this proposed study is to determine whether loss of TRPML1 activity alters neurotransmitter metabolite levels in humans and mice with mucolipidosis IV, aiming to develop a therapeutic biomarker for AAV based gene replacement therapy.

Ace-tRNA readthrough therapy for choroideremia caused by nonsense mutations

Awardee: David M. Gamm

Institution: University of Wisconsin-Madison

Grant Amount: $64,360

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

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Summary:

Choroideremia is a devastating eye disease that leads to progressive loss of vision in 1 in 50,000 males. Currently, there are no approved treatments available for individuals affected by choroideremia. While several research laboratories are working on identifying effective therapies, such work is challenged by the lack of appropriate disease models that would allow clear assessment of the efficacy of a potential therapy. To overcome this impediment, the Gamm lab has developed induced pluripotent stem cell (iPSC)-derived retinal cell and organoid models, which provide a powerful platform for therapeutic testing. As in many other inherited disorders, choroideremia is commonly caused by “nonsense” mutations that prevent formation of full-length functional proteins. The Ahern lab has designed a specialized molecule that allows read-through of many types of these mutations, resulting in full-length protein production. Our goal is to test these read-through molecules in iPSC-derived retinal pigmented epithelial cells and photoreceptors affected by choroideremia in order to advance a new type of therapy for a significant portion of choroideremia patients.

Single-nuclei RNA-seq for CADASIL understanding and therapeutic target discovery

Awardee: Israel Fernández Cadenas

Institution: Fundació Privada Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau

Grant Amount: $60,228

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

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Summary:

The aim of this project is to understand the reason why CADASIL is produced, and possible factors associated with the severity of the disease. To do this, we will use a new and innovative strategy with omic technology (single-nuclei RNA-seq analysis) to obtain transcripts and pathways associated with the disease and its severity. Based on this information, we purpose to find therapeutic targets overexpressing/inhibiting the molecules found to be significant in the single-nuclei RNA-seq study and those found significant in other omic studies of CADASIL already published, to evaluate later the benefits in our human cellular model (pattern of aggregation of Notch3).

Modelling CADASIL with patient iPSC-based 3D vessel-on-chip

Awardee: Saskia Lesnik-Oberstein

Institution: Leiden University Medical Center

Grant Amount: $60,228

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

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Summary:

CADASIL is an hereditary small vessel disease caused by mutations in the NOTCH3 gene. These mutations lead to progressive changes in small brain arteries and reduced blood flow to the brain. Patients with CADASIL suffer from strokes and vascular dementia from mid-adulthood. It has recently been shown by our research group, that some NOTCH3 mutations lead to a much earlier onset of CADASIL than other mutations, but why this is the case is not yet understood. CADASIL vessel models representing both severe and mild mutations will enable us to study the molecular mechanisms underlying these differences and will teach us about CADASIL disease pathomechanisms in general. Our university medical center is a CADASIL expert center and for this project we will collaborate with the internationally leading vessel model group in our research center. Together, we will develop 3D CADASIL vessels-on-chip, built up of CADASIL vascular cells. These cells are obtained by harvesting pluripotent stem cells from blood samples of CADASIL patients with different mutations. The stem cells are then differentiated into vascular cells and incorporated into the chips. We will examine structural and functional abnormalities of the vessel wall and the differences between vessels with severe and mild mutations. We aim to share these CADASIL vessel-on-chip with the international CADASIL research community to promote CADASIL research.

DYSTRO-SMARTY: A novel nanotechnology platform for delivery of nucleic acids to treat Collagen VI-related Congenital Muscular Dystrophy

Awardee: Cecilia Jimenez-Mallebrera

Institution: Hospital Sant Joan de Deu

Grant Amount: $48,876

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

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Summary:

Nucleic-Acid based therapies are being developed at a fast pace with 11 currently approved products and many more in the pipeline. However, delivering therapeutic amounts of these nucleic acids to the target tissue remains the major hurdle, particularly for muscle diseases. Here we propose to apply a validated nanotechnology platform, SMARTY, based on non-liposomal lipid-based nanovesicles, called Quatsomes, to deliver nucleic acids to treat COL6-related Congenital Muscular Dystrophy (COL6-CMD). These nucleic acids are antisense oligonucleotides (ASO) that we have designed and tested to correct a common mutation in collagen VI genes. ASO will be conjugated to the Quatsomes and their physico-chemical properties, distribution and integrity inside the cell as well as their specificity and efficacy to correct collagen VI mutations will be systematically investigated in cells from COL6-CMD patients. The Quatsomes platform (patent WO/2020/229469), developed by our collaborators (at VHIR and ICMAB-CSIC), has already been exploited for other applications for effective intracellular delivery of nucleic acids. Moreover, Quatsomes will be produced by a GMP compliant manufacturing process. This will facilitate the future translation and approval of this potential therapy by regulatory agencies bringing COL6-RD closer to Clinical Trial Readiness.