Repurposed small molecules for use as a bone forming therapeutic during treatment of diseases requiring local bone formation such as fracture repair, spinal fusion, and large segmental bone defects.
- Current treatments require high concentrations of bone morphogenetic protein (BMP) which results in high costs, adverse side effects, and creates a barrier for routine clinical use.
- These novel small molecules modulate a part of the signaling pathway for BMP and can be administered locally to promote bone growth and healing.
- These repurposed therapeutics are already FDA approved for other indications, have minimal side effects, and have a favorable dosing regimen that can be repurposed for local application.
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 is a limited supply of iliac bone, there are substantial costs associated with this surgery, and there are many complications that can develop from this type of bone graft harvesting including pain, nerve damage, and hematoma. BMP is capable of inducing new bone formation and do not require harvesting bone from remote sites of the patient. However BMP must be administered at high doses in order to be effective and these high doses are associated with an increasing number of complications including local edema and bone resorption. 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 BMP.
Through an in silico design and screening process, Emory researchers have identified several candidate small molecules that mimic BMP-receptor interaction. The compounds have already been approved by the FDA for other indications. These compounds have shown activity in an alkaline phosphatase cell based assay enhancing sub-optimal doses of BMP. In addition, several compounds have demonstrated the ability to generate de novo bone formation in a non-bone location in vivo in small rodents.
Candidate small molecules were identified in silico and induction of BMP-receptor activity was validated in vitro in pleuripotent cells.