Awarded Grants

Awarded Grants

MDBR, FDMAS Million Dollar Bike Ride MDBR, FDMAS Million Dollar Bike Ride

Testing the specificity and efficacy of compounds that inhibit cAMP signaling, for the development of potential therapeutics for FD/MAS

Fernando Fierro

University of California Davis

$80,642.00

Awardee: Fernando Fierro

Institution: University of California Davis

Grant Amount: $80,642.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

The Hoffman and Fierro laboratories would like to continue testing compounds to inhibit the excess cAMP production seen in FD/MAS. Proposed studies focus on testing the efficacy and specificity of small molecules, including some candidates identified in the laboratory of our collaborators at UCSF.

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Spatial transcriptomics to elucidate the mechanism of anti-RANKL inhibition of fibrous dysplasia bone lesions

Julia Charles

Brigham and Women's Hospital

$40,321.00

Awardee: Julia Charles

Institution: Brigham and Women's Hospital

Grant Amount: $40,321.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

Fibrous dysplasia causes fibrotic bone lesions, full of immature bone forming osteoblasts, that result in pain, deformity and fracture susceptibility. Antibody that blocks the cytokine RANKL inhibits formation of bone eroding osteoclast cells and also improves bone lesions in fibrous dysplasia, but how this works is not known. We propose to profile what both mutant and bystander wild-type cells are producing before and after RANKL is blocked to try to understand how this treatment works. This is important because blocking RANKL has side effects that limit use and understanding how it improves bone lesions could lead to developing alternative therapies.

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Probing Central and Peripheral Mechanisms of Pain and Dysfunction in Fibrous Dysplasia/McCune-Albright

Jaymin Upadhyay

Boston Children's Hospital

$40,321.00

Awardee: Jaymin Upadhyay

Institution: Boston Children's Hospital

Grant Amount: $40,321.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

Pain remains a multifaceted and often poorly treated symptom in Fibrous Dysplasia/McCune-Albright (FD/MAS). In this project, we propose to identify and treat biopsychosocial or centralized aspects of pain in FD/MAS. We hope to expand upon what is currently understood about pain in FD/MAS and work towards providing improved treatment options to patients with FD/MAS.

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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.

Mara Riminucci

Department of Molecular Medicine, Sapienza University of Rome

$80,000.00

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

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.

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Pain and Analgesic Mechanisms in a Mouse Model of Fibrous Dysplasia

Anne-Marie Heegaard

University of Copenhagen

$80,000.00

Awardee: Anne-Marie Heegaard

Institution: University of Copenhagen

Grant Amount: $80,000.00

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

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.

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

Edward Hsiao

Kelly Wentworth

University of California, San Francisco

$53,791

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

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.

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Structure activity relationship studies of compounds to treat FD/MAS

Fernando Fierro

Charles Hoffman

University of California Davis

$53,791

Awardee: Fernando Fierro

Co-PI: Charles Hoffman

Institution: University of California Davis

Grant Amount: $53,791

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

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.

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

Biagio Palmisano

Sapienza University of Rome

$53,791

Awardee: Biagio Palmisano

Institution: Sapienza University of Rome

Grant Amount: $53,791

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

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.

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Osteoclasts and pain in Fibrous Dysplasia: investigating and targeting the molecular links in a transgenic mouse model (EF1α-GsαR201C mice) of human Fibrous Dysplasia

Mara Riminucci

Sapienza University of Rome

$66,236

Awardee: Mara Riminucci

Institution: Sapienza University of Rome

Award Amount: $66,263

Funding Period: February 1, 2021 - January 31, 2022

Summary:

Osteoclasts are involved in the development and progression of Fibrous Dysplasia of bone (FD). Osteoclasts are skeletal cells that continuously resorb small amount of bone in a tightly regulated way and their function is necessary to allow the growth of the skeleton and its renewal. In FD lesions, osteoclasts remove bone in an uncontrolled manner and interfere with the deposition of normal mineralized bone, thus causing bone fragility. However, osteoclasts formation may not be blocked for long time in the entire skeleton. Using bone biopsies from FD patients and our mouse model of the disease, we previously identified some factors that could stimulate the abnormal formation of osteoclasts within FD lesions and other factors that could mediate their negative effects on bone formation. Therefore, in this project, we will attempt to block these factors in our FD mice in order to eliminate osteoclasts and/or their effects specifically in affected bones. Furthermore, we will start to investigate bone pain associated with the disease in the same mouse model. In particular we will investigate its mechanisms and its changes during the progression of the disease and during the proposed treatments.

 

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