Research Project
7325955
[unreadable] DESCRIPTION (provided by applicant): One of the most challenging problems in clinical Dentistry is the loss of alveolar bone. The primary causes of alveolar bone loss are periodontitis and tooth loss. There is also substantial evidence suggesting that there is a link between alveolar bone loss and osteoporosis, another common disease of the bone in which bone mineral density (BMD) is reduced and bone micro-architecture is disrupted. Nevertheless, current osteoporosis treatments have not been proven to be effective in treating periodontal bone loss. In fact, Bisphosphonates, a class of non-hormone bone-sparing drugs that are most prescribed in treating osteoporosis, have been linked to the development of osteonecrosis of the jaw (ONJ). The absence of effective treatment options for periodontal bone loss has encouraged the continued search for successful therapeutic approaches. Both human and mouse genetic evidence indicates that the Wnt co-receptor LRP5 has an important role in the regulation of bone remodeling. Dickkopf (Dkk), a family of naturally occurring antagonists of the Wnt signaling pathway, functions as a negative regulator for osteogenesis through binding to LRP5. Studies of a high bone mass (HBM) human kindred indicated that the HBM was caused by a LRP5 G171V mutation resulting in abolishing Dkk inhibition of Wnt signaling. The observation that no adverse phenotypes have been detected in humans with this LRP5 mutation, combined with the results from the animal studies with this LRP5 mutation, suggests that the interaction between LRP5 and Dkk can be a potential therapeutic target. In the preliminary studies, we have developed an innovative strategy that combines structural biology, computational screening and biological assays to identify compounds that could disrupt the interaction between Dkk and LRP5 and reverse Dkk-mediated inhibition of the Wnt signaling pathway. One lead compound (Enzo_D58) was shown to stimulate the osteogenic differentiation of cultured primary bone marrow stromal osteoblasts. Locally delivered Enzo_D58 effectively induced calvarial and alveolar new bone formation. In addition, orally administered Enzo_D58 was able to prevent alveolar bone loss in a rat periodontitis model. The oral bioactivity combined with the absence of any observable toxicity makes Enzo_D58 an attractive potential therapeutic agent for alveolar bone loss. In this proposed Phase I study we plan to further explore and validate the therapeutic potentials of the Dkk antagonistic compound Enzo_D58 for preventing alveolar bone loss in animal models. [unreadable] [unreadable] [unreadable]
