Featured Investigators

Kelly Wentworth, MD - Identifying Therapies for Fibrous Dysplasia of the Bone Using a Drug Repositioning Strategy

Figure 1. Radiologic imaging of fibrous dysplastic bone. Left) Craniofacial CT scan of a 33 year old female with FD/MAS, showing extensive fibrous dysplastic bone in the skull (representative lesions, red arrows). Narrowing of the optic canal can be seen in this image (yellow arrow). In addition, this craniofacial lesion shows cystic changes that can be seen in some FD lesions. Right) FD of the right tibia as seen on plain film X ray, of the same patient at age 29.
Figure 2. Drug Repositioning Pipeline. (A) Two gene expression collections: a set of disease expression with corresponding controls and gene expression of tissues treated with drug and corresponding untreated controls. Differential expression disease signature is identified. (B) The disease signature is used to query against the drug reference expression set to assign a drug-disease score for each drug based on profile similarity.  (C) Heatmap depicting several compounds with inverse gene expression profiles to the FD gene expression signature seen in FD-like mice. Green= up-regulated genes; red= down-regulated genes (Drug repositioning figure courtesy of collaborator M. Sirota)

 

Musculoskeletal diseases are the 2nd most common cause of disease burden. These include common conditions like osteoporosis and fractures, but also rare conditions that cause bony deformities and structural weakness. Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS) is a debilitating disease for which there are no directed treatments available. FD/MAS is a somatic, mosaic genetic disease caused by a mutation in GNAS, which encodes the Gs-alpha protein.  This mutation causes constitutive activation of the Gs-GPCR signaling pathway in affected tissues. When the GNAS mutation is expressed in the skeleton, fibrotic, expansile bone lesions form, causing disfigurement, fractures and chronic pain. There are currently no FDA-approved medical therapies designated for FD, and identifying therapies to manage this disease has been extremely challenging. There is an urgent need to find treatments that can target the underlying fibrotic pathology.  Since the pathways that cause FD/MAS are also the same pathways that control bone formation, finding therapies for FD/MAS would also allow us to improve the development of treatments for fractures and osteoporosis.

The overall goal of our CCMBM proposal is to apply a drug repositioning strategy to identify drugs that could potentially reverse or slow fibrotic bone lesion development using single cell RNA sequencing datasets that we generated from human and mouse FD bone lesions.  Drug repositioning is a computational approach that uses disease-specific gene expression profiles generated by -omic datasets to identify candidate drug therapies. We test these candidate drugs on FD bone fibrosis using mouse models. These studies provide an opportunity to find medications that may have benefits for patients with FOP, while revealing new biology that would be helpful for common bone conditions.  We are deeply grateful to the CCMBM/RAP program for supporting this pilot project.

 

Kelly Wentworth, MD

Assistant Professor of Medicine, UCSF

 

Research interests: Understanding the role of Gs-protein coupled receptor signaling in skeletal development, with a focused interest in craniofacial fibrous dysplasia of the bone (FD) and McCune-Albright syndrome (MAS).

 

 


In collaboration with:

Edward Hsiao, MD, PhD

Professor of Medicine, UCSF

Marina Sirota, PhD
Professor of Pediatrics, UCSF
Acting Director, Bakar Computational Health Sciences Institute, UCSF
 

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