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.
Clinical trials for rare diseases like OI are challenging due to lack of supporting models in higher order species, low patient numbers, and a desire to include patients who are free from prior or concurrent drug exposure. Using mouse and human models of the disease, this work will identify factors that limit or enhance the treatment response to sclerostin antibody across a spectrum of OI-causative genes. Thus, the proposed research is relevant to public health because it will help inform which OI patients sclerostin antibody is most likely to benefit, prior to pediatric clinical exposure, and may provide fundamental knowledge towards the mechanism of sclerostin antibody in the treatment of other rare and common pediatric disorders of low bone mass.
