Targeted Bone Regeneration via Activation of Resident Stem Cells

National Center For Advancing Translational Sciences

Investigators

Linked publications, trials & patents

Abstract

More than 1 million severe bone fractures each year fail to heal, resulting in non-union. Current treatments include the use of autografts or bone transport. Limitations associated with autografts harvesting bone from elsewhere in the patients body for use at the site of injury include the need for an additional surgical procedure with the associated morbidity, increased bleeding and operating room time, acute pain during the procedure, and chronic pain post-implant. Bone transport requires an external circular, modular fixator that is fixed to the broken bone via heavy-gauge wires. The fixator allows for partial weight bearing while applying tension to the fractured bone, inducing gradual bone regeneration. Its disadvantages include pain, multiple surgeries, poor patient compliance, inconvenience of the frame, risk of inducing bone malalignment, and a complicated procedure for the surgeon. An alternative approach is the use of bone morphogenetic protein (BMP) to induce bone regeneration. An existing therapy uses BMP-2, but it is mainly used for spinal surgery rather than repair of long bones. Recombinant proteins have short half-lives, requiring large doses that can lead to inflammation and other unwanted side effects. To overcome the limitations of current treatments, the lead collaborators developed a new technology, called SonoHeal, that attracts and activates endogenous tissue stem cells to regenerate bone and heal fractures. First, a biodegradable scaffold is implanted into the fracture site, which recruits the patients own mesenchymal stem cells (MSCs). At a second step, BMP-6 plasmid is delivered to the MSCs via sonoporation the use of transcutaneous ultrasound to transfer plasmid DNA across the cell membrane resulting in BMP-6 protein expression at a physiological level to induce cell differentiation and promote the formation of new bone and fracture healing. TDB scientists have begun preclinical development efforts to advance the SonoHeal technology to clinical evaluation. Ongoing activities include continued development of bioanalytical methods, an in vivo efficacy study, bioanalytical sample analyses to support GLP toxicology studies, pharmacokinetic biodistribution studies, and evaluation of anti-drug antibodies. Completed studies include GMP manufacture of the injectable drug product, pCMV-BMP-6. Completion of all these activities will enable the collaborators to file an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).