This is an application to establish a Brittle Bones Disorders Rare Disease Clinical Research Consortium (BBD RDCRC) focused on studying the over 13 genetic conditions that not contribute to the Osteogenesis Imperfecta (OI) phenotype. The BBD RDCRC is composed of 8 primary clinical sites (Houston, Los Angeles, Portland, Chicago, Montreal, New York City, Baltimore, Washington DC), 2 core sites (Seattle and Tampa), one training &advocacy site (Osteogenesis Imperfecta Foundation), and an Administrative unit (Houston). We propose two clinical projects. Project 1 is a Longitudial study of OI focused on correlating genotype to phenotype, natural history of vertebral fractures in OI type I, scoliosis in severe OI, pregnancy i OI, and craniofacial/dental features in severe Ol. Project 2 is a Phase I trial of an anti-TGFb therapy Fresolimumab in severe OI in the context of a dose ranging study followed by an extension repeat dosing study. There will be two Pilot Projects. The first focuses on the development of mass spectrometric analysis of urinary collagen cross-link patterns as a tool for distinguishing different mechanistic causes of Ol and for correlating with disease severity. The second focuses on validating aspects of the PROMIS tool for adults with OI. An important partner will be the Osteogenesis Imperfecta Foundation (OIF) and the Training and Advocacy activities will be coordianted by the OIF. They include establishment of a new fellowship for clinical research training, a clinical bone research training workshop, and development of a """"""""tool box"""""""" of web-based training for primary healthcare providers to extend the knowledge gained by these studies to patients. Finally, the administration of the BBD RDCRC will be based in Houston at the Baylor College of Medicine. The BBD RDCRC will be leveraged by resources from the OIF who will directly support two of the clinical sites and a pilot project on PROMIS, the Shriners Hospital system, and institutional commitments from Baylor College of Medicine. The BBD RDCRC is built on established cohorts of the OIF Linked Longitudinal Clinical Research Centers and established expertise in pediatric and adult interventional studies that demonstrates a track record of success in patient advocacy, recruitment, and retention for clinical research studies.
Brittle Bone disorders are seen in both genders and all races. These disorders can be devastating and progressive and result in deformity, chronic pain and loss of human potential and life. This study will provide important information about the clinical course of these disorder as well as information which will be useful in optimizing the treatment of these disorders and others.
|Alhamdi, Shatha; Lee, Yi-Chien; Chowdhury, Shimul et al. (2018) Heterozygous WNT1 variant causing a variable bone phenotype. Am J Med Genet A 176:2419-2424|
|Dagdeviren, Didem; Tamimi, Faleh; Lee, Brendan et al. (2018) Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5. Am J Med Genet A :|
|Jain, Mahim; Tam, Allison; Shapiro, Jay R et al. (2018) Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Genet Med :|
|Najirad, Mohammadamin; Ma, Mang Shin; Rauch, Frank et al. (2018) Oral health-related quality of life in children and adolescents with osteogenesis imperfecta: cross-sectional study. Orphanet J Rare Dis 13:187|
|Tam, Allison; Chen, Shan; Schauer, Evan et al. (2018) A multicenter study to evaluate pulmonary function in osteogenesis imperfecta. Clin Genet 94:502-511|
|Lim, Joohyun; Grafe, Ingo; Alexander, Stefanie et al. (2017) Genetic causes and mechanisms of Osteogenesis Imperfecta. Bone 102:40-49|
|Lietman, Caressa D; Lim, Joohyun; Grafe, Ingo et al. (2017) Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. J Bone Miner Res 32:1354-1367|
|Bellur, S; Jain, M; Cuthbertson, D et al. (2016) Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med 18:570-6|
|Grafe, Ingo; Alexander, Stefanie; Yang, Tao et al. (2016) Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res 31:1030-40|
|Lietman, Caressa D; Marom, Ronit; Munivez, Elda et al. (2015) A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res 30:489-98|