SBIR-STTR Award

Osteoporosis affects 55% of Americans over the age of 50, and incurs a medical cost of $47 million a day. It is caused by a disruption in the fine equilibrium between bone resorption and bone deposition. Currently, the most successful pharmaceutical drugs for osteoporosis target bone resorption only, i.e. Oestrogen Therapy & Bisphosphonates. Bone deposition, on the other hand, is now known to be under the control of the WNT pathway co-receptor LRP5. The human high bone mass trait results from a G171V point mutation in LRP5, whereas, the LRP5 loss of function syndrome, OPPG, causes low bone mass. We have isolated a novel secreted molecule, termed Wise, which shares homology with a known human bone density regulator, SOST/Sclerostin. Deficiency of SOST in humans leads to a skeletal disorder characterized by increased bone density due to hyperactive osteoblasts and gain of SOST function in mice leads to a low bone mass phenotype. We have evidence that a deficiency of Wise in mice, as in humans with SOST, leads to an increase in bone density. Others speculate that this effect on bone density is working through inhibition of the Bone Morphogenesis Protein (BMP) pathway. However, we have evidence that Wise and SOST function to modulate bone density by binding to the WNT co-receptor LRP5 but not to LRP5 G171V and inhibiting the WNT pathway in osteoblasts. In vivo studies have shown that pharmacological inhibition of Sost results in increased bone mass with normal bone lamellar structure, serum chemistry, and hematological panels indicate no systemic abnormalities. The goal of Phase I am to identify small organic molecules that neutralize SOST function and increase bone density and quality. We have developed proprietary assays to identify small molecules that block the interaction between SOST and LRP5/6, thus neutralizing SOST function. We have tested our assays and have found them to be effective in identifying specific molecules capable of blocking SOST binding to LRP5/6. We plan to screen a hand picked small molecule library. In Phase II, we will authenticate our positive high throughput hits for specificity of SOST/LRP interaction, and establish/conclude preclinical efficacy of authenticated small molecules.

OsteoGeneX is developing a therapeutic directed against the new bone target Sclerostin (SOST) for the treatment of osteoporosis and related bone disorders. Through genomic approaches Sclerostin was identified as a master regulator of bone mass affecting men and women. Using proteomic approaches Dr. Ellies & Krumlauf discovered and patented Sclerostin's mechanism of action. Since then, Dr. Ellies was awarded an NIH Phase I SBIR ""proof of concept"" grant to screen for compounds that would block SOST function. This library was hand picked by Dr. Gunda Georg, University Distinguished Professor of Medicinal Chemistry, University of Kansas. The NIH has identified Dr. Georg as one of the top 5 percent of researchers receiving funding from the NIH for her work in medicinal chemistry and drug development and discovery. Dr. Ellies has identified many lead candidates that work to block SOST. These candidates need to be authenticated using a novel biochemical approach looking specifically at the binding of SOST to its receptor - LRP5. The binding of these proteins is what regulates new bone formation. Recent news about bone building therapeutics - PTH and analogs - having to carry a black box warning has created a need for a new bone building therapeutic. An alternative to PTH therapy is through the use of Sclerostin as an ideal anabolic target for drug development. The purpose of this SBIR Phase II application is to identify the most optimal dosing of a single or couple of authenticated lead candidates that will build new bone. To accomplish this end, we propose to carry out the following specific aims; authenticate positive lead candidates; calculate effective dosage and delivery; and analyze their effect in rat models for osteoporosis.

Public Health Relevance:
Osteoporosis is one of the most prevalent problems in our society. New drug targets for controlling bone deposition must be identified, as our understanding of the molecular control of bone deposition is poor. While there is no cure for osteoporosis, the FDA has approved the use of certain drugs to prevent and treat osteoporosis. These drugs, especially those directed against bone resorption, cause undesirable side effects and may not significantly reduce fracture risk in the target populations. Thus, there is a critical need to identify new and better therapeutics that would result in better patient outcomes. This proposal is aimed at authenticating novel drugs that increase bone deposition, rather than prevent resorption, to offset the bone loss of osteoporosis. Furthermore, this proposal will establish a dosage regime & delivery, and show proof of concept in animals.

Public Health Relevance:
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