MICA: Recruitment of endogenous stem cells by targeted up-regulation of early inflammation to promote healing of fragility fractures

Fractures of osteoporotic bones are a major and increasing clinical problem with our aging population. Worldwide, every year there are 200 million people at risk of fragility fractures and over 1.6 million hip fractures, which have a mortality rate of more than 20% in the first year alone. Accelerating the repair of these fractures will reduce the considerable morbidity and mortality in this vulnerable group of patients. Yet there is currently no approved therapy to achieve this. Furthermore, orthopaedic implants used to fix the fractures to restore functional anatomy and enable early mobilisation tend to not attach to or cut out of the weakened osteoporotic bone.

Using tissue discarded at surgery from patients with severe open leg fractures, we found that pro-inflammatory cytokines normally released at the fracture site attract the body's own stem cells and induce them to make bone. This exciting observation provides a simpler, safer, quicker and cheaper alternative repair strategy to cell-based therapy, which involves growing and genetically manipulating stem cells in the lab and reintroducing them back into the patient. Using an established animal model, we showed that local addition of the cytokine, TNF, during the early phase of fracture healing, leads to significantly faster healing. We have gone on to demonstrate that this is also the case for fractures of fragile osteoporotic bone. We have also developed a murine model using a screw implant that is routinely used in clinical practice to assess whether local administration of TNF improves implant attachment in weakened bone.

This grant proposal will enable the development of a safe, reproducible delivery strategy for therapy to accelerate repair of weak osteoporotic bone. The collaboration between the Kennedy Institute, University of Oxford, UK, and Halozyme Therapeutics, USA, will allow us to produce a formulation to accurately deliver TNF at the fracture or orthopaedic implant site. The formulation, comprising constituents already approved for clinical use, will be injectable and tested on cells followed by animal studies that are specifically designed to mimic the problems found in the clinic, including various types of fragile bone. By the conclusion of this work, we will have all the results necessary to proceed to clinical trials for accelerating the healing of fractures and improving implant adherence in osteoporotic bone to deliver clinical benefit to needy patients.

Stem cells underpin healing and repair in all tissues. They may be harnessed to promote repair by culture and ex vivo activation before re-introduction, although this approach poses problems of cost and scalability as well as safety if the cells are virally transduced to overexpress growth factors. Our proposal aims to address the urgent unmet need to accelerate the healing of fragility fractures and improve implant adherence in osteoporotic bone by recruiting endogenous stem cells from a variety of local sources and inducing their osteogenic differentiation. This strategy also overcomes the time delay in expanding cells in vitro that precludes the treatment of fragility fractures, eg of the femoral neck, that should be treated surgically within 36hrs of injury for optimal clinical outcomes

Our published data demonstrate that targeted up-regulation of inflammation by local administration of TNF at the fracture site accelerates healing and our preliminary data shows that this also pertains to osteoporotic fractures. We will validate these findings for fractures in mice rendered osteoporotic by oophorectomy as well as in Cushingoid animals. Surgical fixation of osteoporotic fractures often fails due to cut-out or pull-through of implants. We will also assess the effect of TNF administration on transosseous screw adherence. We currently administer TNF in PBS by local injection; however, this dissipates rapidly. In collaboration with Halozyme Therapeutics, we will develop the technology to precisely administer TNF using a FDA-approved carrier that is in a liquid phase at low temperatures and therefore suitable for injection. However it forms a gel at body temperature and hence will localize TNF to the fracture site for maximal efficacy. The preparations will be evaluated using our existing animal models that emulate the clinical problems encountered by reconstructive surgeons. Development and validation of this methodology will allow us to proceed to clinical trials

Development of the first effective therapeutic that is administered locally at the fracture site and acts by recruiting endogenous stem cells to accelerate the healing of fragility fractures and adherence of orthopaedic implants in osteoporotic bone will have a major health benefit for millions of patients across the globe. Shortened hospital stays as well as reduced morbidity and mortality rates will markedly reduce direct as well as indirect health and social care costs. The cost of fragility fractures in the UK was estimated at £1.7 billion in the year 2000 alone.

Our preliminary discussions with the pharmaceutical industry have indicated that whilst there is keen interest in developing cytokine therapy for accelerating fracture healing, a major limiting factor is the current lack of a delivery mechanism that can be translated to the clinical arena. A major aspect of our proposal is to formulate a preparation that is suitable for routine clinical use and test it in murine models that emulate the clinical situation. Our collaboration with Halozyme will therefore provide a synergistic translational approach to develop the first therapeutic to accelerate fracture repair and implant adherence in osteoporotic bone to set the stage for clinical trails which we are able to perform in the nationally recognised trauma centre in Oxford.