Craniosynostoses are a group of congenital disorders which involve the premature fusion of one or more of the cranial sutures, causing cessation or distortion of craniofacial growth. Increased intracranial pressure is the most critical complication, often resulting in poor intellectual development as well as alterations in vision. The prevalence of these disorders is 1:1000 live births and they can occur alone, or in association with craniofacial syndromes, such as Crouzon or Apert. To allow for adequate craniofacial growth and brain development, excision of the fused suture(s) is the treatment of choice. Unfortunately, re-ossification of the excised suture is common and necessitates several surgical procedures throughout childhood. A therapeutic agent which could prevent re-ossification of the excised sutures by transiently blocking osteogenesis would be an effective adjunct to surgery. Therefore, this study will investigate the effect on cranial suture ossification of a novel anti-osteogenic agent delivered in a collagen gel. Fibronectin (FN), an extracellular matrix molecule, has been shown to play an essential role in calvarial osteoblast osteogenesis. Anti-FN antibodies, soluble cell-binding FN fragments and anti-FN receptor antibodies are all FN antagonists which have been shown to selectively and reversibly block osteogenesis. Preliminary studies utilizing a well-characterized rat calvarial organ culture system have demonstrated that anti-FN antibodies, in particular, can inhibit cranial suture fusion. Preliminary experiments also demonstrated that the delivery system, a collagen gel vehicle, can transfer the active antibody to cranial suture sites and is retained over time.
In Aim 1 we will use this novel approach to identify FN antagonists that can prevent suture fusion in rabbit calvarial organ culture. The candidate reagents will be evaluated to determine their optimal suture-perturbing influence and working concentrations prior to in vivo rabbit studies.
In Aim 2 we will determine characteristics of the collagen vehicle which will enhance the retention and delivery of reagents in a normal rabbit animal model. Together, studies in Aims 1 and 2 will provide a cost-efficient and time-saving method to identify and optimize the most effective suture perturbing reagents.
In Aim 3 the FN antagonist selected from studies conducted in Aims 1 and 2 will be delivered to craniosynostotic rabbits to assess its ability to prevent cranial suture re-ossification. Together, these studies will 1) produce an effective screening method for potential cranial suture-perturbing reagents, 2) provide valuable information on the biology of cranial suture formation and 3) determine the potential for therapeutic applications of FN antagonists in the treatment of craniosynostosis.
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| Premaraj, S; Mundy, B; Parker-Barnes, J et al. (2005) Collagen gel delivery of Tgf-beta3 non-viral plasmid DNA in rat osteoblast and calvarial culture. Orthod Craniofac Res 8:320-2 |
