Abstracts

Rationale: : Recently several genes have been associated with Landau-Kleffner syndrome, including PLAUR, FOXP2, and SPRX2. Among these, a mouse model lacking Plaur has previously been shown to exhibit sporadic seizures and aberrant forebrain anatomy. The endophenotypes of the Plaur null mouse may reflect symptoms of Landau-Kleffner syndrome. Postnatal genetic supplementation of hepatocyte growth factor (HGF) has been shown to remediate the seizure and anxiety phenotypes of the Plaur null mouse. In this study, we investigate ways to supplement the perinatal brain with HGF as a therapeutic agent.Methods: The goal is to restore the aberrant neural circuitry by engineering a degradable biocompatible delivery system. The approach is based on cyclic acetal chemistry (5-ethyl-5(hydroxymethyl)-B,B-dimethyl-1,3-dioxane-2-ethanol diacrylate 9(EHD)) and poly (ethylene gycol ) diacylate (PEGDA) that has been developed, with previous success in delivering growth factors for in situ bone regeneration. Results: We demonstrate the feasibility of using this system for the release of human HGF. Two loading mechanisms, surface loading and encapsulation, were investigated and the release profiles characterized over multiple days. Release profiles of surface loaded gels show approximately 30-40% mass were released. For encapsulated HGF-samples, approximately 3 -15% mass were released. Additional in vitro experiments confirm biocompatibility of the constructs and bioactivity of the released HGF.Conclusions: HGF can be released at biologically significant levels. Ongoing studies are investigating the degradation kinetics and immune responses to the polymers in vivo.