Research Project
6882204
DESCRIPTION (provided by applicant): Repair of large structural bone defects remains a major problem in orthopaedic reconstruction surgery due to the limited supply of cortical bone autograft and the poor long-term outcomes obtained with structural allografts. While there is no substitute for structural allografts, based on their biomechanical and biocompatible properties, their lack of osteogenic and osteoinductive potential, combined with the host's inability to remodel processed cortical bone, results in a high percentage of fractures. Towards the development and commercialization of the first revitalizing structural allograft, Asklepios Inc. and LAGeT Inc. have enter into a partnership that will combine core competencies in recombinant adeno-associated virus (rAAV) mediated gene transfer with orthopaedic pre-clinical and clinical development. In collaboration, we have established a murine model of femoral allograft healing and demonstrated that first generation rAAV vectors can be freeze-dried onto the cortical surface of femoral allografts and efficiently transduce proximal cells in vivo following transplantation. Furthermore, we have shown the feasibility of this approach to revitalized processed structural allografts using a constitutively active type I BMP receptor (caAlk2) target gene. Based on this success, here we propose three requisite studies towards commercialization: Specific Aim 1, to identify the optimal rAAV serotype; Specific Aim 2, to determine the optimal titer of rAAV/mmS allograft; and Specific Aim 3, perform an efficacy study that will yield quantitative micro-CT and histomorphometry data on new bone formation over the allograft that can be used to formulate methodologies and power calculations for large animal pre-clinical and clinical trials. While this application focuses on a very specific indication that has a very low prevalence, the rAAV serotype and coating technologies have enormous potential to prevent host rejection and improve engraftment and healing of all implantable and surgical materials. Thus, our success here will open many areas of investigation and opportunities in all areas of medicine.
