Treating osteogenesis imperfecta by inhibiting the PRC2 complex

The goal of this proposal is to develop a new strategy for skeletal regeneration in patients who have osteogenesis imperfecta (OI) or brittle bone disease using epigenetics regulators that alter gene expression. We have shown that inhibiting a epigenetic regulator, PCR2, increases bone formation in normal mice and will determine if this also occurs in OI mice. We will also investigate if a small molecule that inhibits the PRC2 complex can also increase bone formation in OI mice and cells from OI patients.

Year 1 Progress Report:

Our laboratory works on an inherited bone disorder called osteogenesis imperfecta or OI that leads to brittle bones and other complications including dentinogenesis imperfecta (teeth abnormalities), hearing loss, blue sclera, cardiovascular abnormalities, easy bruising, and scoliosis.  These complications can lead to multiple fractures, inability to walk independently, significant pain from fractures, and in some case even death shortly after birth.  We have found that altering a specific pathway in the cell can lead to increased bone formation in normal mice.  This project will determine if altering this same pathway in mice with OI will increase bone mass and reduce fractures in the mice.  If we can demonstrate this potential for therapy in OI patients, there are already available drugs that inhibit this pathway that could be tested.  The goal of this project is to lay the groundwork for the use of these drugs in a clinical trial for OI.  The last year has been difficult for everyone and that includes those of us working in research.  The COVID-19 pandemic has limited our ability to accomplish the task that we had hope to complete.  Many laboratories had to shut down all projects except for required laboratory maintenance which made it difficult to start and advance new projects.  Obtaining the required resources from outside institutions were challenging due to pandemic related concerns.  Also, there were limits placed on hiring as it was unclear what the financial strain the pandemic may have placed on the institution.  Now with the environment improving, we expect to fully commit to our tasks laid out in this proposal.