Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Meeting, September 26–27, 2018: A Meeting in Affiliation With the American Society for Bone and Mineral Research (ASBMR)

A rare disease in the US is defined as a condition that affects fewer than 200,000 Americans. Similar numerical definitions are found in other countries with the vast majority of them being caused by genetic mutations that are transmitted in Mendelian fashion. Increasingly powerful genomic technologies such as next-generation sequencing have led to the identification of close to 4000 disease-associated genes and more than 7000 phenotypes associated with mutations in these genes. The following collection of abstracts were presented in the recent conference co-organized by the Rare Bone Diseases Alliance, the Osteogenesis Imperfecta Foundation, and the Brittle Bone Disorders Consortium of the NIH Rare Diseases Clinical Research Consortia on the Mechanistic and Therapeutic Advances of Rare Skeletal Diseases on September 26–27 in Montreal, Canada. The purpose of the conference, held in partnership with the American Society for Bone and Mineral Research Annual Meeting, was to bring together clinicians and basic, translational, and clinical researchers interested in rare genetic disorders affecting the skeleton and to provide a forum for state-of-the-art talks on the current state of diagnosis, preclinical models and mechanistic basis of disease, therapeutic strategies in the clinical arena, and novel endpoints and assessments. The initial session focused on diagnostic approaches to rare skeletal diseases ranging from classical radiographic and ultrasonographic approaches to multi-omic approaches based on next-generation DNA sequencing, RNA sequencing, and metabolomics; evaluation of chromatin architecture in controlling gene expression in the context of translating rare genetic mutation to common bone phenotypes; and finally, analysis of protein modifications of macromolecules such as collagens in the pathogenesis of bone disease. These talks underscored the importance of multidimensional approaches to phenotyping rare skeletal diseases for not only diagnosis but also for generating hypotheses to guide mechanistic studies focused on disease pathogenesis. These mechanistic studies have taken advantage of diverse preclinical models, though mouse models have been especially powerful in the context of skeletal diseases, particularly those manifested in alterations in bone structure. This is likely due to the relative evolutionary conservation of the structural requirements of skeletal function. This is in contrast to the translational obstacles in the diseases that affect organs such as the immune system or the brain where functional conservation is less pronounced. These rapid advances were exemplified by the mechanistic observations found in diseases like fibrous dysplasia, fibrodysplasia ossificans progressiva (FOP), osteogenesis imperfecta, progressive heterotopic ossification, multiple osteochondroma (hereditary multiple exostoses), craniosynostosis, osteopetrosis, and hypodontia. In all of these models, preclinical studies have led to pathways that may be targeted for treatment. A challenge in the translation of such discoveries is the identification of small molecules that can affect such pathways. One promising approach is the broad area of chemical biology, where diverse approaches have been developed to both screen for specific interactions as well as target specific amino acid residues posttranslationally to achieve either gain or loss of function. An alternative to small molecule–based targeting is biological therapies such as transplantation of stem cells. Here, targeted tissues and locations such as in the dental niche may offer the best early disease targets. Emerging disease mechanisms such as in Melorheostosis and Gorham's disease may offer new targets for such approaches. Targeting signaling pathways in rare skeletal diseases has been most effectively translated into the clinical arena by manipulating downstream mechanistic alterations. Excellent examples of this approach include anti-TGFβ treatment in osteogenesis imperfecta caused by collagen-related alterations, anti-sclerostin in osteoporosis and osteogenesis imperfecta, and anti-FGF23 in X-linked hypophosphatemic (XLH) rickets due to mutations in PHEX. Alternatively, ligand-mediated activation of the C-natriuretic pathway is being clinically studied for treatment of achondroplasia due FGFR3 mutations. Ultimately, clinical developments in rare skeletal diseases will require incorporation of endpoints that inform clinical outcomes. Promising technologies focused on bone mass include high-resolution peripheral quantitative computed tomography (HR-pQCT), MRI evaluation of cartilage in diseases that present with osteoarthritis, and potentially effective novel biomarkers of the growth plate for disorders of skeletal growth. Ultimately, close partnership with the FDA in the evidence-based evaluation of such endpoints will be critical for moving effective therapies to the clinic. An excellent example of this has been the development of composite radiographical endpoints in the evaluation of hypophosphatasia. Finally, partnership with industry is also essential for moving mechanistic discoveries to patients. Successful examples of these interactions include the development of anti-FGF23 therapy in XLH and Asfotase Alfa in hypophosphatasia. Others in the pipeline include clinical study of palovarotene in FOP and multiple osteochondroma, and anti-sclerostin in osteogenesis imperfecta. Ultimately, in addition to efficacy, we must also begin to address obstacles to patient access and economic impact of these and future exciting therapies in the rare skeletal disease field. Acknowledgments The meeting received unrestricted support from the following companies: Alexion, Regeneron, Clementia, MereoBioPharma, Ultragenyx, Sanofi Genzyme, Blueprint Medicines, and Therachon. Support was also provided by these patient advocacy organizations: Fibrous Dysplasia Foundation, The MHE Research Foundation, Osteogenesis Imperfecta Foundation, International Fibrodysplasia Progressiva Association, Soft Bones Foundation, Lymphatic Malformation Institute, The Melorheostosis Association, Lymphangiomatosis & Gorham's Disease Alliance, and the XLH Network. Supporting partners were ICCBH and Shriners International. Funding for this conference was made possible in part by 1-R13AR074876-01 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and co-funding support from the National Institute of Dental and Craniofacial Research (NIDCR), the National Center for Advancing Translational Sciences and the National Institute on as meeting from the for to the and the for of and for Skeletal Diseases The rapid advances in next-generation sequencing technologies have a rapid in in rare skeletal are close to 4000 disease genes but more than of novel caused by mutations in the gene Mendelian in of these clinical phenotypes skeletal is for discoveries in skeletal development and the importance of the diagnostic impact on these to protein loss of and the of to diverse skeletal approaches to were based on targeted DNA next-generation sequencing for analysis of and sequencing has the of analysis of and new gene as well as identification of phenotypes due to part of the NIH Diseases the of Clinical has a multi-omic approach to diagnosis, sequencing and of and sequencing has mutations that have the to and analysis of and RNA of skeletal genes and with of by a multi-omic approach sequencing and can the of diagnostic in rare skeletal diseases as well as to novel that will inform of studies have for skeletal genomic and not the of with to only a of such that of the offer to that in likely a and to on the of we have on a high-resolution to the interactions of all in In we are generating chromatin to for for of the common to in a skeletal we are well to to to such by genes such in the context can genetic of and of Skeletal Diseases in genomic technologies have of the and basis of The to disease with less particularly radiographic is This is particularly to the in the of DNA in the has for diagnosis of as well as for a for radiographic and in skeletal diseases, particularly in novel on of diseases, and following of disease treatment. has also provided on skeletal development in the of radiographic can by the with the skeletal of the particularly in genes or pathways that have skeletal and a in a of and skeletal of and of Bone and of bone and cartilage are potentially in the diagnosis and of of skeletal disease, rare of current and new approaches to target disease-associated of the skeleton will be The will be on and of osteogenesis imperfecta, in most of is that can provide a on the of bone by bone are will be mass the of to and can the of osteogenesis imperfecta on bone These are of genetic of this be in to therapy for in clinical from and that are in the mass screen provide quantitative in of and potentially in other skeletal The and recent will be National Institute of Dental and Craniofacial Research Fibrous and Fibrous is a skeletal disease caused by of mutations in the of and are associated with is but recent that with to is the with that and are to like cells. are of fibrous and of of and can affect or skeleton with and that include and in with is by a in a in bone and a in the radiographic with and is not with skeletal or mutation is associated with and skeletal In models bone and skeletal have provided These include for and the of and signaling in the of in have pathway and and are being to and screen to and are mouse that all and in the of the and of of the and of the mutation in skeletal to these models can address the basis of pathway activation the mechanisms of skeletal stem the of the and of the the biological of in in and to and models and in preclinical of and the and of in Fibrodysplasia Progressiva Fibrodysplasia ossificans progressiva is genetic by but of heterotopic bone in skeletal and FOP is caused by mutations in bone protein with of the A in the mechanisms that heterotopic in FOP was the that a as on and is for the and of the heterotopic bone In of A to a and effectively with for of A A in mouse models of and models the most of FOP to in of in we have with to the development of the heterotopic bone and to the of A have that by this early can be and with and the with the growth of the and as the of A incorporation of into heterotopic bone a of for the of signaling for the and growth of heterotopic bone in technologies will be in the context of observations in the mouse and in clinical will be Shriners of Osteogenesis Imperfecta Osteogenesis imperfecta is a bone of other are in more than to have been associated with of with a clinical of have a mutation that is by analysis of these genes. though most with have bone as by bone is in most of of gene the This may to the of the bone in the with have bone and bone with such as a therapeutic though the is in than the bone is also associated with mass and function. 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