Bone forming therapeutic for use in spinal fusion devices and treatment of systemic bone diseases and disorders.
- Current devices for bone grafting procedures require high concentrations of bone morphogenetic protein (BMP) which results in a high cost and create a barrier for routine clinical use.
- Small molecule therapeutics that inhibit noggin (an extracellular inhibitor of BMP) have been identified and could be used locally to promote bone formation.
It is estimated that approximately 2.2 million bone grafting procedures are performed worldwide each year with an estimated cost of these procedures approaching $2.5 billion per year. For spinal fusions, more than 250,000 procedures are performed in the US each year and the bone healing failure rate may be as high as 40%. The iliac crest is often used as a donor site for autologous grafts but there are many complications that can develop from this type of bone graft harvesting including pain, nerve damage, and hematoma. There is also limited supply of iliac bone as well as substantial cost associated with this surgery. Bone morphogenetic proteins (BMP) are being used increasingly in orthopedic surgeries. These small molecules are capable of inducing new bone formation when delivered in the appropriate concentration and on the appropriate scaffold and do not require harvesting bone from remote sites of the patient. The FDA has approved several devices including INFUSETM which is used in spinal surgeries and has yielded over $3 billion in sales since its 2002 FDA approval. The high cost and need for high concentrations of BMP create barriers for routine clinical use so there is a need for other compounds that can substitute or complement the use of BMPs.
Noggin is an extracellular protein that regulates the activity of BMPs by binding them and preventing them from binding their cell surface receptors which is require to initiate the BMP signaling pathway. In addition, Noggin is produced in response to BMP as presumably a part of a negative feedback loop that can limit the effectiveness of exogenously applied BMPs. Interruption of Noggin function should result in increased responsiveness to BMPs and as a result, could be used locally to promote bone and cartilage formation in response to BMP. By inhibiting Noggin, the patient's dose of BMP required may be reduced (thus decreasing local side effects) and perhaps enhance less potent bone inducers to encourage cells to become active osteoblasts without the use of exogenous BMPs. Through an in silico design and screening process, Emory researchers have identified several lead compounds to perform this function. The two lead compounds have shown activity to enhance BMP function in a reporter assay system and in an alkaline phosphatase cell based assay.