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Biologic signatures for sclerostin antibody responsiveness in human and murine models of osteogenesis imperfecta

人类和小鼠成骨不全模型中硬化素抗体反应性的生物学特征

基本信息

批准号：
9912070
负责人：
Kenneth M Kozloff
金额：
$ 20.59万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-09 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912070
关键词：
Address Affect Anabolism Antibodies Antibody Therapy Architecture Biological Biomechanics Bone Diseases Bone structure Cellular Structures Characteristics Childhood Clinical Clinical Data Clinical Drug Development Clinical Treatment Clinical Trials Collagen Type I DNA Sequence Alteration Defect Disease Disease model Drug Exposure Environment Equilibrium Extracellular Matrix Foundations Future Genes Genetic Genetic Models Genetic Transcription Genotype Goals Harvest Heterogeneity Human Hydroxylation Image Implant Individual Intervention Knowledge Location Measures Medical Genetics Modeling Mus Mutation Nude Mice Operative Surgical Procedures Orthopedic Procedures Osteoblasts Osteoclasts Osteogenesis Osteogenesis Imperfecta Outcome Outcome Study Pathogenesis Patients Pharmacology Phenotype Population Predictive Factor Public Health Rare Diseases Research Risk Rodent Role Sampling Severities Signal Transduction Skeleton Splice-Site Mutation Structure Surface Techniques Testing Time Tissues Treatment Efficacy Treatment Factor Up-Regulation Validation Variant WNT Signaling Pathway Work Xenograft Model Xenograft procedure base bone bone cell bone fragility bone mass bone strength cortical bone differential expression exposed human population extracellular high reward high risk human model improved innovation mouse model novel novel strategies patient response personalized medicine pre-clinical prevent response skeletal disorder subcutaneous substantia spongiosa transplant model treatment planning treatment response

项目摘要

Abstract Sclerostin antibody therapy represents a paradigm-shifting strategy for treating the low bone mass and high bone fragility characteristic of pediatric osteogenesis imperfecta (OI). However, it remains unknown how the variation in OI pathogenesis and severity contribute to sclerostin antibody efficacy. There is a compelling need to identify the regulatory factors that are responsible for sclerostin antibody efficacy in models of OI that can span the gap between pre-clinical genetic mouse studies and human clinical trials prior to pediatric clinical exposure. The goal of this proposal is to identify biologic signatures that regulate the anabolic efficacy of sclerostin antibody across a broad spectrum of OI-causative genes. Based on an extensive set of pre-clinical data, we hypothesize that sclerostin antibody can induce osteoblastic bone formation to a common anabolic maximum, independent of the underlying causative OI defect, given sufficient baseline bone architecture to support surface-based bone modeling. Aim 1 will test this hypothesis by treating sclerostin antibody efficacy across a panel of mice representing major causative genetic defects of OI including structural and splice-site mutations in type I collagen, and deficits in prolyl hydroxylation and c-propeptide cleavage. We will assess cortical and trabecular bone response to sclerostin antibody by nanoCT imaging and biomechanical testing and assess osteoblastic response to treatment using static and dynamic histomorphometry. Transcriptional differences across genotype and in response to treatment will assess the role of compensatory changes in osteoblast or osteoclast signaling cascades that could enhance or limit treatment efficacy. This aim balances a low-risk approach with a high-risk hypothesis that, even if proven false, will provide a high-value outcome—for the first time in our research, we expect to identify factors tied to underlying OI genotype and phenotype that govern sclerostin antibody treatment efficacy in genetic models of the disorder. In Aim 2, we will validate these predictive factors in a recently developed xenograft transplantation model that allows for testing of sclerostin antibody treatment response in bone sampled directly from OI patients. Bone samples acquired from OI patients during surgical procedures will be implanted subcutaneously into nude mice and treated with sclerostin antibody. Structural, cellular, and transcriptional changes will be assessed to confirm mechanistic findings from Aim 1. This aim presents a high-risk experimental approach balanced by potential for a high- reward outcome that will confirm factors of treatment efficacy in a model that may be used to directly assess patient-specific response to therapy. If successful, we anticipate these findings will generate foundational evidence that will improve our understanding of the efficacy and limitations of sclerostin antibody in the treatment of OI and potentially other pediatric diseases of low bone mass. Furthermore, through the patient xenograft model, outcomes from these studies may support a platform to assess personalized medicine opportunities in a disease of high heterogeneity which may be used to guide and support future clinical trials.

摘要