Wnt antagonists for treatment and prevention of osteoporosis
Inventors: Xi He, Chika Yokota, Xinjun Zhang, Bryan MacDonald
Invention Types: Therapeutics
Research Areas: Musculoskeletal, Oncology/Hematology
Keywords: Large MoleculeFor More Information Contact: Ives, Catherine L.
The inventors have identified new Wnt inhibitors, TIKI1 and TIKI2, expressed by the Tiki1 and Tiki2 genes, respectively. This invention relates to these proteins and nucleic acids, cells expressing the same, and methods for identifying compounds that modulate TIKI1/2 activity for use in the treatment of osteoporosis, bone fractures or cellular proliferative disorders such as cancer.
The TIKI proteins antagonize Wnt signaling by acting as Wnt-specific proteases that cleaves the amino-terminus of Wnt proteins, thereby inactivating them. TIKI1 and 2 are transmembrane proteins, and act in both Wnt-producing cells and Wnt-responsive cells. TIKI proteins are unique among known Wnt antagonists in that they are enzymes that inactivate Wnt proteins, whereas all other known Wnt antagonists, e.g. DKK-1 and SOST, inhibit Wnt-binding to receptors via protein-protein interaction.
The inventors first identified the TIKI proteins in Xenopus and both Tiki1 and Tiki2 genes are found in human, rabbit and fish. Rodents only have one Tiki gene, Tiki2. In mice experiments, TIKI2 protein is expressed in osteoblasts postnatally and the Tiki2 gene homozygous knock-out mice exhibit high bone mass, suggesting that TIKI2, like Sclerostin, DKK1, and SFRP1, may be an important negative regulator of bone homeostasis.
- Therapy and prevention for osteoporosis, capable of bone regeneration for patients with bone loss
- Treatment of bone fractures
- Cancer therapeutic
Osteoporosis is a major public health threat for an estimated 44 million Americans or 55 percent of the people 50 years of age and older. In the U.S. today, 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis.
Small chemical compound inhibitors remain most attractive drug candidates for treating osteoporosis or disorders associated with unwanted cellular proliferation, e.g., cancer. However, the known Wnt antagonists such as Sclerostin, DKK1, and SFRP1 function through protein-protein interactions and their inhibition via small molecules is difficult to achieve. On the contrary TIKI2 appears to be an ideal therapeutic target for several reasons. First, Tiki2-/- , or even Tiki2+/-, mice show increased bone mass, suggesting that inhibition, or even partial inhibition, of TIKI2 may benefit osteoporosis treatment. Second, Tiki2-/- mice are viable, suggesting that long-term TIKI inhibition may have minimal adverse effects. Third, TIKI proteins act as enzymes, which in general are ‘drugable’, i.e., suitable for inhibition by chemical compounds.
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Key Publications: Zhang X, et al. Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell. 2012 Jun 22;149(7):1565-77.
Zhang X, et al. Characterization of Tiki, a new family of Wnt-specific metalloproteases. J Biol Chem. 2016 Jan 29;291(5):2435-43.
IPStatus: Pat. Pend.